Mary E. Norton, MD

Cerebral palsy (CP) is the most common cause of severe neurodisability in children, and it occurs in about 2 to 3 per 1,000 births worldwide.¹ This nonprogressive disorder is characterized by symptoms that include spasticity, dystonia, choreoathetosis, and/or ataxia that are evident in the first few years of life. While many perinatal variables have been associated with CP, in most cases a specific cause is not identified.

Other neurodevelopmental disorders, such as intellectual disability, epilepsy, and autism spectrum disorder, are often associated with CP.² These other neurodevelopmental disorders are often genetic, and this has raised the question as to whether CP also might have a substantial genetic component, although this has not been investigated in any significant way until recently. This topic is of great interest to the obstetric community, given that CP often is attributed to obstetric events, including mismanagement of labor and delivery.

Emerging evidence of a genetic-CP association

In an article published recently in JAMA, Moreno-De-Luca and colleagues sought to determine the diagnostic yield of exome sequencing for CP.³ This large cross-sectional study included results of exome sequencing performed in 2 settings. The first setting was a commercial laboratory in which samples were sent for analysis due to a diagnosis of CP, primarily in children (n = 1,345) with a median age of 8.8 years. A second cohort, recruited from a neurodevelopmental disorders clinic at Geisinger, included primarily adults (n = 181) with a median age of 41.9 years.

As is standard in exome sequencing, results were considered likely causative if they were classified as pathogenic or likely pathogenic based on criteria of the American College of Genetics and Genomics. In the laboratory group, 32.7% (440 of 1,345) had a genetic cause of the CP identified, while in the clinic group, 10.5% (19 of 181) had a genetic etiology found. Although most of the identified genetic variants were de novo (that is, they arose in the affected individual and were not clearly inherited), some were inherited from carrier parents.³

A number of other recent studies also have investigated genetic causes of CP and similarly have reported that a substantial number of cases are genetic. Several studies that performed chromosomal microarray analysis in individuals with CP found deleterious copy number variants in 10% to 31% of cases.^4-6 Genomic variants detectable by exome sequencing have been reported in 15% to 20% of cases.³ In a recent study in Nature Genetics, researchers performed exome sequencing on 250 parent-child “trios” in which the child had CP, and they found that 14% of cases had an associated genetic variant that was thought to be causative.⁴ These studies all provide consistent evidence that a substantial proportion of CP cases are due to genetic causes.

Contributors to CP risk

Historically, CP was considered to occur largely as a result of perinatal anoxia. In 1862, the British orthopedic surgeon William John Little first reported an association between prematurity, asphyxia, difficult delivery, and CP in a paper presented to the Obstetrical Society of London.⁷ Subsequently, much effort has gone into the prevention of perinatal asphyxia and birth injury, although our ability to monitor fetal well-being remains limited. Nonreassuring fetal heart rate patterns are nonspecific and can occur for many reasons other than fetal asphyxia. Studies of electronic fetal monitoring have found that continuous monitoring primarily leads to an increase in cesarean delivery with no decrease in CP or infant mortality.⁸

While some have attributed this to failure to accurately interpret the fetal heart rate tracing, it also may be because a substantial number of CP cases are due to genetic and other causes, and that very few in fact result from preventable intrapartum injury.

The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics agree that knowledge gaps preclude definitive determination that a given case of neonatal encephalopathy is attributable to an acute intrapartum event, and they provide criteria that must be fulfilled to establish a reasonable causal link between an intrapartum event and subsequent long-term neurologic disability.⁹ However, there continues to be a belief in the medical, scientific, and lay communities that birth asphyxia, secondary to adverse intrapartum events, is the leading cause of CP. A “brain-damaged infant” remains one of the most common malpractice claims, and birth injury one of the highest paid claims. Such claims generally allege that intrapartum asphyxia has caused long-term neurologic sequelae, including CP.

While it is true that prematurity, infection, hypoxia-ischemia, and pre- and perinatal stroke all have been implicated as contributing to CP risk, large population-based studies have shown that birth asphyxia accounts for less than 12% of CP cases.¹⁰ Specifically, recent data indicate that acute intrapartum hypoxia-ischemia occurs only in about 6% of CP cases. In other words, it does occur and may contribute to some cases, but this is likely a smaller percent than previously thought, and genetic factors now appear to be far more significant contributors.¹¹

Continue to: Exploring a genetic etiology...

In considering the etiologies of CP, it is important to note that 21% to 40% of individuals with CP have an associated congenital anomaly, suggesting a genetic origin in at least some individuals. Moreover, a 40% heritability has been estimated in CP, which is comparable to the heritability rate for autism spectrum disorders.¹²

In the recent study by Moreno-De-Luca and colleagues, some of the gene variants detected were previously associated with other forms of neurodevelopmental disability, such as epilepsy and autism spectrum disorder.³ Many individuals in the study cohort were found to have multiple neurologic comorbidities, for example, CP as well as epilepsy, autism spectrum disorder, and/or intellectual disability. The presence of these additional comorbidities increased the likelihood of finding a genetic cause; the authors found that the diagnostic yield ranged from 11.2% with isolated CP to 32.9% with all 3 comorbidities. The yield was highest with CP and intellectual disability and CP with all 3 comorbidities. A few genes were particularly common, and some were reported previously in association with CP and/or other neurodevelopmental disorders. In some patients, variants were found in genes or gene regions associated with disorders that do not frequently include CP, such as Rett syndrome.³

Implications for ObGyns

The data from the study by Moreno-De-Luca and colleagues are interesting and relevant to pediatricians, neurologists, and geneticists, as well as obstetricians. Understanding the cause of any disease or disorder improves care, including counseling regarding the cause, the appropriate interventions or therapy, and in some families, the recurrence risk in another pregnancy. The treatment for CP has not changed significantly in many years. Increasingly, detection of an underlying genetic cause can guide precision treatments; thus, the detection of specific gene variants allows a targeted approach to therapy.

Identification of a genetic cause also can significantly impact recurrence risk counseling and prenatal diagnosis options in another pregnancy. In general, the empiric recurrence risk of CP is quoted as 1% to 2%,¹³ and with de novo variants this does not change. However, with inherited variants the recurrence risk in future children is substantially higher. While 72% of the genetic variants associated with CP in the Moreno-De-Luca study were de novo with a low recurrence risk, in the other 28% the mode of inheritance indicated a substantial risk of recurrence (25%–50%) in another pregnancy.³ Detecting such causative variant(s) allows not only accurate counseling about recurrence risk but also preimplantation genetic testing or prenatal diagnosis when recurrence risk is high.

In the field of obstetrics, the debate about the etiology of CP is important largely due to the medicolegal implications. Patient-oriented information on the internet often states that CP is caused by damage to the child’s brain just before, during, or soon after birth, supporting potential blame of those providing care during those times. Patient-oriented websites regarding CP do not list genetic disorders among the causes but rather include primarily environmental factors, such as prematurity, low birth weight, in utero infections, anoxia or other brain injury, or perinatal stroke. Even the Centers for Disease Control and Prevention website lists brain damage as the primary etiology of CP.¹⁴ Hopefully, these new data will increase a broader understanding of this condition.

Exome sequencing is now recommended as a first-tier test for individuals with many neurodevelopmental disorders, including epilepsy, intellectual disability, and autism spectrum disorder.¹⁵ However, comprehensive genetic testing is not typically recommended or performed in cases of CP. Based on recent data, including the report by Moreno-De-Luca and colleagues, it would seem that CP should be added to the list of disorders for which exome sequencing is ordered, given the similar prevalence and diagnostic yield. ●

Cerebral palsy (CP) is the most common cause of severe neurodisability in children, and it occurs in about 2 to 3 per 1,000 births worldwide.¹ This nonprogressive disorder is characterized by symptoms that include spasticity, dystonia, choreoathetosis, and/or ataxia that are evident in the first few years of life. While many perinatal variables have been associated with CP, in most cases a specific cause is not identified.

Other neurodevelopmental disorders, such as intellectual disability, epilepsy, and autism spectrum disorder, are often associated with CP.² These other neurodevelopmental disorders are often genetic, and this has raised the question as to whether CP also might have a substantial genetic component, although this has not been investigated in any significant way until recently. This topic is of great interest to the obstetric community, given that CP often is attributed to obstetric events, including mismanagement of labor and delivery.

Emerging evidence of a genetic-CP association

In an article published recently in JAMA, Moreno-De-Luca and colleagues sought to determine the diagnostic yield of exome sequencing for CP.³ This large cross-sectional study included results of exome sequencing performed in 2 settings. The first setting was a commercial laboratory in which samples were sent for analysis due to a diagnosis of CP, primarily in children (n = 1,345) with a median age of 8.8 years. A second cohort, recruited from a neurodevelopmental disorders clinic at Geisinger, included primarily adults (n = 181) with a median age of 41.9 years.

As is standard in exome sequencing, results were considered likely causative if they were classified as pathogenic or likely pathogenic based on criteria of the American College of Genetics and Genomics. In the laboratory group, 32.7% (440 of 1,345) had a genetic cause of the CP identified, while in the clinic group, 10.5% (19 of 181) had a genetic etiology found. Although most of the identified genetic variants were de novo (that is, they arose in the affected individual and were not clearly inherited), some were inherited from carrier parents.³

A number of other recent studies also have investigated genetic causes of CP and similarly have reported that a substantial number of cases are genetic. Several studies that performed chromosomal microarray analysis in individuals with CP found deleterious copy number variants in 10% to 31% of cases.^4-6 Genomic variants detectable by exome sequencing have been reported in 15% to 20% of cases.³ In a recent study in Nature Genetics, researchers performed exome sequencing on 250 parent-child “trios” in which the child had CP, and they found that 14% of cases had an associated genetic variant that was thought to be causative.⁴ These studies all provide consistent evidence that a substantial proportion of CP cases are due to genetic causes.

Contributors to CP risk

Historically, CP was considered to occur largely as a result of perinatal anoxia. In 1862, the British orthopedic surgeon William John Little first reported an association between prematurity, asphyxia, difficult delivery, and CP in a paper presented to the Obstetrical Society of London.⁷ Subsequently, much effort has gone into the prevention of perinatal asphyxia and birth injury, although our ability to monitor fetal well-being remains limited. Nonreassuring fetal heart rate patterns are nonspecific and can occur for many reasons other than fetal asphyxia. Studies of electronic fetal monitoring have found that continuous monitoring primarily leads to an increase in cesarean delivery with no decrease in CP or infant mortality.⁸

While some have attributed this to failure to accurately interpret the fetal heart rate tracing, it also may be because a substantial number of CP cases are due to genetic and other causes, and that very few in fact result from preventable intrapartum injury.

The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics agree that knowledge gaps preclude definitive determination that a given case of neonatal encephalopathy is attributable to an acute intrapartum event, and they provide criteria that must be fulfilled to establish a reasonable causal link between an intrapartum event and subsequent long-term neurologic disability.⁹ However, there continues to be a belief in the medical, scientific, and lay communities that birth asphyxia, secondary to adverse intrapartum events, is the leading cause of CP. A “brain-damaged infant” remains one of the most common malpractice claims, and birth injury one of the highest paid claims. Such claims generally allege that intrapartum asphyxia has caused long-term neurologic sequelae, including CP.

While it is true that prematurity, infection, hypoxia-ischemia, and pre- and perinatal stroke all have been implicated as contributing to CP risk, large population-based studies have shown that birth asphyxia accounts for less than 12% of CP cases.¹⁰ Specifically, recent data indicate that acute intrapartum hypoxia-ischemia occurs only in about 6% of CP cases. In other words, it does occur and may contribute to some cases, but this is likely a smaller percent than previously thought, and genetic factors now appear to be far more significant contributors.¹¹

Continue to: Exploring a genetic etiology...

In considering the etiologies of CP, it is important to note that 21% to 40% of individuals with CP have an associated congenital anomaly, suggesting a genetic origin in at least some individuals. Moreover, a 40% heritability has been estimated in CP, which is comparable to the heritability rate for autism spectrum disorders.¹²

In the recent study by Moreno-De-Luca and colleagues, some of the gene variants detected were previously associated with other forms of neurodevelopmental disability, such as epilepsy and autism spectrum disorder.³ Many individuals in the study cohort were found to have multiple neurologic comorbidities, for example, CP as well as epilepsy, autism spectrum disorder, and/or intellectual disability. The presence of these additional comorbidities increased the likelihood of finding a genetic cause; the authors found that the diagnostic yield ranged from 11.2% with isolated CP to 32.9% with all 3 comorbidities. The yield was highest with CP and intellectual disability and CP with all 3 comorbidities. A few genes were particularly common, and some were reported previously in association with CP and/or other neurodevelopmental disorders. In some patients, variants were found in genes or gene regions associated with disorders that do not frequently include CP, such as Rett syndrome.³

Implications for ObGyns

The data from the study by Moreno-De-Luca and colleagues are interesting and relevant to pediatricians, neurologists, and geneticists, as well as obstetricians. Understanding the cause of any disease or disorder improves care, including counseling regarding the cause, the appropriate interventions or therapy, and in some families, the recurrence risk in another pregnancy. The treatment for CP has not changed significantly in many years. Increasingly, detection of an underlying genetic cause can guide precision treatments; thus, the detection of specific gene variants allows a targeted approach to therapy.

Identification of a genetic cause also can significantly impact recurrence risk counseling and prenatal diagnosis options in another pregnancy. In general, the empiric recurrence risk of CP is quoted as 1% to 2%,¹³ and with de novo variants this does not change. However, with inherited variants the recurrence risk in future children is substantially higher. While 72% of the genetic variants associated with CP in the Moreno-De-Luca study were de novo with a low recurrence risk, in the other 28% the mode of inheritance indicated a substantial risk of recurrence (25%–50%) in another pregnancy.³ Detecting such causative variant(s) allows not only accurate counseling about recurrence risk but also preimplantation genetic testing or prenatal diagnosis when recurrence risk is high.

In the field of obstetrics, the debate about the etiology of CP is important largely due to the medicolegal implications. Patient-oriented information on the internet often states that CP is caused by damage to the child’s brain just before, during, or soon after birth, supporting potential blame of those providing care during those times. Patient-oriented websites regarding CP do not list genetic disorders among the causes but rather include primarily environmental factors, such as prematurity, low birth weight, in utero infections, anoxia or other brain injury, or perinatal stroke. Even the Centers for Disease Control and Prevention website lists brain damage as the primary etiology of CP.¹⁴ Hopefully, these new data will increase a broader understanding of this condition.

Exome sequencing is now recommended as a first-tier test for individuals with many neurodevelopmental disorders, including epilepsy, intellectual disability, and autism spectrum disorder.¹⁵ However, comprehensive genetic testing is not typically recommended or performed in cases of CP. Based on recent data, including the report by Moreno-De-Luca and colleagues, it would seem that CP should be added to the list of disorders for which exome sequencing is ordered, given the similar prevalence and diagnostic yield. ●

Cerebral palsy (CP) is the most common cause of severe neurodisability in children, and it occurs in about 2 to 3 per 1,000 births worldwide.¹ This nonprogressive disorder is characterized by symptoms that include spasticity, dystonia, choreoathetosis, and/or ataxia that are evident in the first few years of life. While many perinatal variables have been associated with CP, in most cases a specific cause is not identified.

Other neurodevelopmental disorders, such as intellectual disability, epilepsy, and autism spectrum disorder, are often associated with CP.² These other neurodevelopmental disorders are often genetic, and this has raised the question as to whether CP also might have a substantial genetic component, although this has not been investigated in any significant way until recently. This topic is of great interest to the obstetric community, given that CP often is attributed to obstetric events, including mismanagement of labor and delivery.

Emerging evidence of a genetic-CP association

In an article published recently in JAMA, Moreno-De-Luca and colleagues sought to determine the diagnostic yield of exome sequencing for CP.³ This large cross-sectional study included results of exome sequencing performed in 2 settings. The first setting was a commercial laboratory in which samples were sent for analysis due to a diagnosis of CP, primarily in children (n = 1,345) with a median age of 8.8 years. A second cohort, recruited from a neurodevelopmental disorders clinic at Geisinger, included primarily adults (n = 181) with a median age of 41.9 years.

As is standard in exome sequencing, results were considered likely causative if they were classified as pathogenic or likely pathogenic based on criteria of the American College of Genetics and Genomics. In the laboratory group, 32.7% (440 of 1,345) had a genetic cause of the CP identified, while in the clinic group, 10.5% (19 of 181) had a genetic etiology found. Although most of the identified genetic variants were de novo (that is, they arose in the affected individual and were not clearly inherited), some were inherited from carrier parents.³

A number of other recent studies also have investigated genetic causes of CP and similarly have reported that a substantial number of cases are genetic. Several studies that performed chromosomal microarray analysis in individuals with CP found deleterious copy number variants in 10% to 31% of cases.^4-6 Genomic variants detectable by exome sequencing have been reported in 15% to 20% of cases.³ In a recent study in Nature Genetics, researchers performed exome sequencing on 250 parent-child “trios” in which the child had CP, and they found that 14% of cases had an associated genetic variant that was thought to be causative.⁴ These studies all provide consistent evidence that a substantial proportion of CP cases are due to genetic causes.

Contributors to CP risk

Historically, CP was considered to occur largely as a result of perinatal anoxia. In 1862, the British orthopedic surgeon William John Little first reported an association between prematurity, asphyxia, difficult delivery, and CP in a paper presented to the Obstetrical Society of London.⁷ Subsequently, much effort has gone into the prevention of perinatal asphyxia and birth injury, although our ability to monitor fetal well-being remains limited. Nonreassuring fetal heart rate patterns are nonspecific and can occur for many reasons other than fetal asphyxia. Studies of electronic fetal monitoring have found that continuous monitoring primarily leads to an increase in cesarean delivery with no decrease in CP or infant mortality.⁸

While some have attributed this to failure to accurately interpret the fetal heart rate tracing, it also may be because a substantial number of CP cases are due to genetic and other causes, and that very few in fact result from preventable intrapartum injury.

The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics agree that knowledge gaps preclude definitive determination that a given case of neonatal encephalopathy is attributable to an acute intrapartum event, and they provide criteria that must be fulfilled to establish a reasonable causal link between an intrapartum event and subsequent long-term neurologic disability.⁹ However, there continues to be a belief in the medical, scientific, and lay communities that birth asphyxia, secondary to adverse intrapartum events, is the leading cause of CP. A “brain-damaged infant” remains one of the most common malpractice claims, and birth injury one of the highest paid claims. Such claims generally allege that intrapartum asphyxia has caused long-term neurologic sequelae, including CP.

While it is true that prematurity, infection, hypoxia-ischemia, and pre- and perinatal stroke all have been implicated as contributing to CP risk, large population-based studies have shown that birth asphyxia accounts for less than 12% of CP cases.¹⁰ Specifically, recent data indicate that acute intrapartum hypoxia-ischemia occurs only in about 6% of CP cases. In other words, it does occur and may contribute to some cases, but this is likely a smaller percent than previously thought, and genetic factors now appear to be far more significant contributors.¹¹

Continue to: Exploring a genetic etiology...

In considering the etiologies of CP, it is important to note that 21% to 40% of individuals with CP have an associated congenital anomaly, suggesting a genetic origin in at least some individuals. Moreover, a 40% heritability has been estimated in CP, which is comparable to the heritability rate for autism spectrum disorders.¹²

In the recent study by Moreno-De-Luca and colleagues, some of the gene variants detected were previously associated with other forms of neurodevelopmental disability, such as epilepsy and autism spectrum disorder.³ Many individuals in the study cohort were found to have multiple neurologic comorbidities, for example, CP as well as epilepsy, autism spectrum disorder, and/or intellectual disability. The presence of these additional comorbidities increased the likelihood of finding a genetic cause; the authors found that the diagnostic yield ranged from 11.2% with isolated CP to 32.9% with all 3 comorbidities. The yield was highest with CP and intellectual disability and CP with all 3 comorbidities. A few genes were particularly common, and some were reported previously in association with CP and/or other neurodevelopmental disorders. In some patients, variants were found in genes or gene regions associated with disorders that do not frequently include CP, such as Rett syndrome.³

Implications for ObGyns

The data from the study by Moreno-De-Luca and colleagues are interesting and relevant to pediatricians, neurologists, and geneticists, as well as obstetricians. Understanding the cause of any disease or disorder improves care, including counseling regarding the cause, the appropriate interventions or therapy, and in some families, the recurrence risk in another pregnancy. The treatment for CP has not changed significantly in many years. Increasingly, detection of an underlying genetic cause can guide precision treatments; thus, the detection of specific gene variants allows a targeted approach to therapy.

Identification of a genetic cause also can significantly impact recurrence risk counseling and prenatal diagnosis options in another pregnancy. In general, the empiric recurrence risk of CP is quoted as 1% to 2%,¹³ and with de novo variants this does not change. However, with inherited variants the recurrence risk in future children is substantially higher. While 72% of the genetic variants associated with CP in the Moreno-De-Luca study were de novo with a low recurrence risk, in the other 28% the mode of inheritance indicated a substantial risk of recurrence (25%–50%) in another pregnancy.³ Detecting such causative variant(s) allows not only accurate counseling about recurrence risk but also preimplantation genetic testing or prenatal diagnosis when recurrence risk is high.

In the field of obstetrics, the debate about the etiology of CP is important largely due to the medicolegal implications. Patient-oriented information on the internet often states that CP is caused by damage to the child’s brain just before, during, or soon after birth, supporting potential blame of those providing care during those times. Patient-oriented websites regarding CP do not list genetic disorders among the causes but rather include primarily environmental factors, such as prematurity, low birth weight, in utero infections, anoxia or other brain injury, or perinatal stroke. Even the Centers for Disease Control and Prevention website lists brain damage as the primary etiology of CP.¹⁴ Hopefully, these new data will increase a broader understanding of this condition.

Exome sequencing is now recommended as a first-tier test for individuals with many neurodevelopmental disorders, including epilepsy, intellectual disability, and autism spectrum disorder.¹⁵ However, comprehensive genetic testing is not typically recommended or performed in cases of CP. Based on recent data, including the report by Moreno-De-Luca and colleagues, it would seem that CP should be added to the list of disorders for which exome sequencing is ordered, given the similar prevalence and diagnostic yield. ●

Prenatal diagnosis of genetic anomalies is important for diagnosing lethal genetic conditions before birth. It can provide information for parents regarding pregnancy options and allow for recurrence risk counseling and the potential use of preimplantation genetic testing in the next pregnancy. For decades, a karyotype was used to analyze amniocentesis and chorionic villus sampling specimens; in recent years, chromosomal microarray analysis provides more information about significant chromosomal abnormalities, including microdeletions and microduplications. However, microarrays also have limitations, as they do not identify base pair changes associated with single-gene disorders.

The advent of next-generation sequencing has substantially reduced the cost of DNA sequencing. Whole genome sequencing (WGS) can sequence the entire genome— both the coding (exonic) and noncoding (intronic) regions—while exome sequencing analyzes only the protein-coding exons, which make up 1% to 2% of the genome and about 85% of the protein-coding genes associated with known human disease. Exome sequencing increasingly is used in cases of suspected genetic disorders when other tests have been unrevealing.

In this Update, we review recent reports of prenatal exome sequencing, including studies exploring the yield in fetuses with structural anomalies; the importance of prenatal phenotyping; the perspectives of parents and health care professionals who were involved in prenatal exome sequencing studies; and a summary of a joint position statement from 3 societies regarding prenatal sequencing.

Prenatal whole exome sequencing has potential utility, with some limitations 

Petrovski S, Aggarwal V, Giordano JL, et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet. 2019;393:758-767. 
 

Lord J, McMullan DJ, Eberhardt RY, et al; for the Prenatal Assessment of Genomes and Exomes Consortium. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet. 2019;393:747-757. 

Exome sequencing has been shown to identify an underlying genetic cause in 25% to 30% of children with an undiagnosed suspected genetic disorder. Two studies recently published in the Lancet sought to determine the incremental diagnostic yield of prenatal whole exome sequencing (WES) in the setting of fetal structural anomalies when karyotype and microarray results were normal. 

Continue to: Details of the studies...

In a prospective cohort study by Petrovski and colleagues, DNA samples from 234 fetuses with a structural anomaly (identified on ultrasonography) and both parents (parent-fetus "trios") were used for analysis. WES identified diagnostic genetic variants in 24 trios (10%). An additional 46 (20%) had variants that indicated pathogenicity but without sufficient evidence to be considered diagnostic. 

The anomalies with the highest frequency of a genetic diagnosis were lymphatic, 24%; skeletal, 24%; central nervous system, 22%; and renal, 16%; while cardiac anomalies had the lowest yield at 5%. 

In another prospective cohort study, known as the Prenatal Assessment of Genomes and Exomes (PAGE), Lord and colleagues sequenced DNA samples from 610 parent-fetus trios, but they restricted sequencing to a predefined list of 1,628 genes. Diagnostic genetic variants were identified in 52 fetuses (8.5%), while 24 (3.9%) had a variant of uncertain significance that was thought to be of potential clinical usefulness. 

Fetuses with multiple anomalies had the highest genetic yield (15.4%), followed by skeletal (15.4%) and cardiac anomalies (11.1%), with the lowest yield in fetuses with isolated increased nuchal translucency (3.2%). 

Diagnostic yield is high, but prenatal utility is limited 

Both studies showed a clinically significant diagnostic yield of 8% to 10% for prenatal exome sequencing in cases of fetal structural anomalies with normal karyotype and microarray testing. While this yield demonstrates the utility of prenatal exome sequencing, it is significantly lower than what has been reported in postnatal studies. One of the reasons for this is the inherent limitation of prenatal phenotyping (discussed below). 

The importance of prenatal phenotyping 

Aarabi M, Sniezek O, Jiang H, et al. Importance of complete phenotyping in prenatal whole exome sequencing. Hum Genet. 2018;137:175-181. 

In postnatal exome sequencing, the physical exam, imaging findings, and laboratory results are components of the phenotype that are used to interpret the sequencing data. Prenatal phenotyping, however, is limited to the use of fetal ultrasonography and, occasionally, the addition of magnetic resonance imaging. Prenatal phenotyping is without the benefit of an exam to detect more subtle anomalies or functional status, such as developmental delay, seizures, or failure to thrive. 

When a structural anomaly is identified on prenatal ultrasonography, it is especially important that detailed imaging be undertaken to detect other anomalies, including more subtle facial features and dysmorphology. 

Value of reanalyzing exome sequencing data 

Aarabi and colleagues conducted a retrospective study of 20 fetuses with structural anomalies and normal karyotype and microarray. They performed trio exome sequencing first using information available only prenatally and then conducted a reanalysis using information available after delivery. 

With prenatal phenotyping only, the investigators identified no pathogenic, or likely pathogenic, variants. On reanalysis of combined prenatal and postnatal findings, however, they identified pathogenic variants in 20% of cases. 

Significance of the findings 

This study highlights both the importance of a careful, detailed fetal ultrasonography study and the possible additional benefit of a postnatal examination (such as an autopsy) in order to yield improved results. In addition, the authors noted that the development of a prenatal phenotype-genotype database would significantly help exome sequencing interpretation in the prenatal setting.

Social impact of WES: Parent and provider perspectives 

Wou K, Weitz T, McCormack C, et al. Parental perceptions of prenatal whole exome sequencing (PPPWES) study. Prenat Diagn. 2018;38:801-811. 

Horn R, Parker M. Health professionals' and researchers' perspectives on prenatal whole genome and exome sequencing: 'We can't shut the door now, the genie's out, we need to refine it.' PLoS One. 2018;13:e0204158. 

As health care providers enter a new era of prenatal genetic testing with exome sequencing, it is crucial to the path forward that we obtain perspectives from the parents and providers who participated in these studies. Notably, in both of the previously discussed Lancet reports, the authors interviewed the participants to discuss the challenges involved and identify strategies for improving future testing. 

Continue to: What parents want...

To ascertain the perceptions of couples who underwent prenatal WES, Wou and colleagues conducted semi-structured interviews with participants from the Fetal Sequencing Study regarding their experience. They interviewed 29 parents from 17 pregnancies, including a mix of those who had pathogenic prenatal results, terminated prior to receiving the results, and had normal results. 
 

Expressed feelings and desires. Parents recalled feelings of anxiety and stress around the time of diagnosis and the need for help with coping while awaiting results. The majority of parents reported that they would like to be told about uncertain results, but that desire decreased as the certainty of results decreased. 

Parents were overall satisfied with the prenatal genetic testing experience, but they added that they would have liked to receive written materials beforehand and a written report of the test results (including negative cases). They also would like to have connected with other families with similar experiences, to have received results sooner, and to have an in-person meeting after telephone disclosure of the results. 

Health professionals articulate complexity of prenatal genomics 

In a qualitative interview study to explore critical issues involved in the clinical practice use of prenatal genomics, Horn and Parker conducted interviews with 20 health care professionals who were involved in the previously described PAGE trial. Patient recruiters, midwives, genetic counselors, research assistants, and laboratory staff were included. 

Interviewees cited numerous challenges involved in their day-to-day work with prenatal whole genome and exome sequencing, including: 

• the complexity of achieving valid parental consent at a time of vulnerability 
• management of parent expectations  
• transmitting and comprehending complex information 
• the usefulness of information 
• the difficulty of a long turnaround time for study results. 

All the interviewees agreed that prenatal exome sequencing studies contribute to knowledge generation and the advancement of technology. 

The authors concluded that an appropriate next step would be the development of appropriate guidelines for good ethical practice that address the concerns encountered in genomics clinical practice.

Societies offer guidance on using genome and exome sequencing 

International Society for Prenatal Diagnosis, Society for Maternal and Fetal Medicine, Perinatal Quality Foundation. Joint Position Statement from the International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality Foundation (PQF) on the use of genome-wide sequencing for fetal diagnosis. Prenat Diagn. 2018;38:6-9. 

In response to the rapid integration of exome sequencing for genetic diagnosis, several professional societies—the International Society for Prenatal Diagnosis, Society for Maternal Fetal Medicine, and Perinatal Quality Foundation—issued a joint statement addressing the clinical use of prenatal diagnostic genome wide sequencing, including exome sequencing. 

Continue to: Guidance at a glance...

The societies' recommendations are summarized as follows: 

• Exome sequencing is best done as a trio analysis, with fetal and both parental samples sequenced and analyzed together. 
• Extensive pretest education, counseling, and informed consent, as well as posttest counseling, are essential. This should include:  

—the types of results to be conveyed (variants that are pathogenic, likely pathogenic, of uncertain significance, likely benign, and benign) 
—the possibility that results will not be obtained or may not be available before the birth of the fetus 
—realistic expectations regarding the likelihood that a significant result will be obtained 
—the timeframe to results 
—the option to include or exclude in the results incidental or secondary findings (such as an unexpected childhood disorder, cancer susceptibility genes, adult-onset disorders) 
—the possibility of uncovering nonpaternity or consanguinity 
—the potential reanalysis of results over time 
—how data are stored, who has access, and for what purpose. 

• Fetal sequencing may be beneficial in the following scenarios: 

—multiple fetal anomalies or a single major anomaly suggestive of a genetic disorder, when the microarray is negative 
—no microarray result is available, but the fetus exhibits a pattern of anomalies strongly suggestive of a single-gene disorder  
—a prior undiagnosed fetus (or child) with anomalies suggestive of a genetic etiology, and with similar anomalies in the current pregnancy, with normal karyotype or microarray. Providers also can consider sequencing samples from both parents prior to preimplantation genetic testing to check for shared carrier status for autosomal recessive mutations, although obtaining exome sequencing from the prior affected fetus (or child) is ideal. 
—history of recurrent stillbirths of unknown etiology, with a recurrent pattern of anomalies in the current pregnancy, with normal karyotype or microarray. 

• Interpretation of results should be done using a multidisciplinary team-based approach, including clinical scientists, geneticists, genetic counselors, and experts in prenatal diagnosis. 
• Where possible and after informed consent, reanalysis of results should be undertaken if a future pregnancy is planned or ongoing, and a significant amount of time has elapsed since the time the result was last reported. 
• Parents should be given a written report of test results. 

Summary

Exome sequencing is increasingly becoming mainstream in postnatal genetic testing, and it is emerging as the newest diagnostic frontier in prenatal genetic testing. However, there are limitations to prenatal exome sequencing, including issues with consent at a vulnerable time for parents, limited information available regarding the phenotype, and results that may not be available before the birth of a fetus. Providers should be familiar with the indications for testing, the possible results, the limitations of prenatal phenotyping, and the implications for future pregnancies. 
 

Prenatal diagnosis of genetic anomalies is important for diagnosing lethal genetic conditions before birth. It can provide information for parents regarding pregnancy options and allow for recurrence risk counseling and the potential use of preimplantation genetic testing in the next pregnancy. For decades, a karyotype was used to analyze amniocentesis and chorionic villus sampling specimens; in recent years, chromosomal microarray analysis provides more information about significant chromosomal abnormalities, including microdeletions and microduplications. However, microarrays also have limitations, as they do not identify base pair changes associated with single-gene disorders.

The advent of next-generation sequencing has substantially reduced the cost of DNA sequencing. Whole genome sequencing (WGS) can sequence the entire genome— both the coding (exonic) and noncoding (intronic) regions—while exome sequencing analyzes only the protein-coding exons, which make up 1% to 2% of the genome and about 85% of the protein-coding genes associated with known human disease. Exome sequencing increasingly is used in cases of suspected genetic disorders when other tests have been unrevealing.

In this Update, we review recent reports of prenatal exome sequencing, including studies exploring the yield in fetuses with structural anomalies; the importance of prenatal phenotyping; the perspectives of parents and health care professionals who were involved in prenatal exome sequencing studies; and a summary of a joint position statement from 3 societies regarding prenatal sequencing.

Prenatal whole exome sequencing has potential utility, with some limitations 

Petrovski S, Aggarwal V, Giordano JL, et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet. 2019;393:758-767. 
 

Lord J, McMullan DJ, Eberhardt RY, et al; for the Prenatal Assessment of Genomes and Exomes Consortium. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet. 2019;393:747-757. 

Exome sequencing has been shown to identify an underlying genetic cause in 25% to 30% of children with an undiagnosed suspected genetic disorder. Two studies recently published in the Lancet sought to determine the incremental diagnostic yield of prenatal whole exome sequencing (WES) in the setting of fetal structural anomalies when karyotype and microarray results were normal. 

Continue to: Details of the studies...

In a prospective cohort study by Petrovski and colleagues, DNA samples from 234 fetuses with a structural anomaly (identified on ultrasonography) and both parents (parent-fetus "trios") were used for analysis. WES identified diagnostic genetic variants in 24 trios (10%). An additional 46 (20%) had variants that indicated pathogenicity but without sufficient evidence to be considered diagnostic. 

The anomalies with the highest frequency of a genetic diagnosis were lymphatic, 24%; skeletal, 24%; central nervous system, 22%; and renal, 16%; while cardiac anomalies had the lowest yield at 5%. 

In another prospective cohort study, known as the Prenatal Assessment of Genomes and Exomes (PAGE), Lord and colleagues sequenced DNA samples from 610 parent-fetus trios, but they restricted sequencing to a predefined list of 1,628 genes. Diagnostic genetic variants were identified in 52 fetuses (8.5%), while 24 (3.9%) had a variant of uncertain significance that was thought to be of potential clinical usefulness. 

Fetuses with multiple anomalies had the highest genetic yield (15.4%), followed by skeletal (15.4%) and cardiac anomalies (11.1%), with the lowest yield in fetuses with isolated increased nuchal translucency (3.2%). 

Diagnostic yield is high, but prenatal utility is limited 

Both studies showed a clinically significant diagnostic yield of 8% to 10% for prenatal exome sequencing in cases of fetal structural anomalies with normal karyotype and microarray testing. While this yield demonstrates the utility of prenatal exome sequencing, it is significantly lower than what has been reported in postnatal studies. One of the reasons for this is the inherent limitation of prenatal phenotyping (discussed below). 

The importance of prenatal phenotyping 

Aarabi M, Sniezek O, Jiang H, et al. Importance of complete phenotyping in prenatal whole exome sequencing. Hum Genet. 2018;137:175-181. 

In postnatal exome sequencing, the physical exam, imaging findings, and laboratory results are components of the phenotype that are used to interpret the sequencing data. Prenatal phenotyping, however, is limited to the use of fetal ultrasonography and, occasionally, the addition of magnetic resonance imaging. Prenatal phenotyping is without the benefit of an exam to detect more subtle anomalies or functional status, such as developmental delay, seizures, or failure to thrive. 

When a structural anomaly is identified on prenatal ultrasonography, it is especially important that detailed imaging be undertaken to detect other anomalies, including more subtle facial features and dysmorphology. 

Value of reanalyzing exome sequencing data 

Aarabi and colleagues conducted a retrospective study of 20 fetuses with structural anomalies and normal karyotype and microarray. They performed trio exome sequencing first using information available only prenatally and then conducted a reanalysis using information available after delivery. 

With prenatal phenotyping only, the investigators identified no pathogenic, or likely pathogenic, variants. On reanalysis of combined prenatal and postnatal findings, however, they identified pathogenic variants in 20% of cases. 

Significance of the findings 

This study highlights both the importance of a careful, detailed fetal ultrasonography study and the possible additional benefit of a postnatal examination (such as an autopsy) in order to yield improved results. In addition, the authors noted that the development of a prenatal phenotype-genotype database would significantly help exome sequencing interpretation in the prenatal setting.

Social impact of WES: Parent and provider perspectives 

Wou K, Weitz T, McCormack C, et al. Parental perceptions of prenatal whole exome sequencing (PPPWES) study. Prenat Diagn. 2018;38:801-811. 

Horn R, Parker M. Health professionals' and researchers' perspectives on prenatal whole genome and exome sequencing: 'We can't shut the door now, the genie's out, we need to refine it.' PLoS One. 2018;13:e0204158. 

As health care providers enter a new era of prenatal genetic testing with exome sequencing, it is crucial to the path forward that we obtain perspectives from the parents and providers who participated in these studies. Notably, in both of the previously discussed Lancet reports, the authors interviewed the participants to discuss the challenges involved and identify strategies for improving future testing. 

Continue to: What parents want...

To ascertain the perceptions of couples who underwent prenatal WES, Wou and colleagues conducted semi-structured interviews with participants from the Fetal Sequencing Study regarding their experience. They interviewed 29 parents from 17 pregnancies, including a mix of those who had pathogenic prenatal results, terminated prior to receiving the results, and had normal results. 
 

Expressed feelings and desires. Parents recalled feelings of anxiety and stress around the time of diagnosis and the need for help with coping while awaiting results. The majority of parents reported that they would like to be told about uncertain results, but that desire decreased as the certainty of results decreased. 

Parents were overall satisfied with the prenatal genetic testing experience, but they added that they would have liked to receive written materials beforehand and a written report of the test results (including negative cases). They also would like to have connected with other families with similar experiences, to have received results sooner, and to have an in-person meeting after telephone disclosure of the results. 

Health professionals articulate complexity of prenatal genomics 

In a qualitative interview study to explore critical issues involved in the clinical practice use of prenatal genomics, Horn and Parker conducted interviews with 20 health care professionals who were involved in the previously described PAGE trial. Patient recruiters, midwives, genetic counselors, research assistants, and laboratory staff were included. 

Interviewees cited numerous challenges involved in their day-to-day work with prenatal whole genome and exome sequencing, including: 

• the complexity of achieving valid parental consent at a time of vulnerability 
• management of parent expectations  
• transmitting and comprehending complex information 
• the usefulness of information 
• the difficulty of a long turnaround time for study results. 

All the interviewees agreed that prenatal exome sequencing studies contribute to knowledge generation and the advancement of technology. 

The authors concluded that an appropriate next step would be the development of appropriate guidelines for good ethical practice that address the concerns encountered in genomics clinical practice.

Societies offer guidance on using genome and exome sequencing 

International Society for Prenatal Diagnosis, Society for Maternal and Fetal Medicine, Perinatal Quality Foundation. Joint Position Statement from the International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality Foundation (PQF) on the use of genome-wide sequencing for fetal diagnosis. Prenat Diagn. 2018;38:6-9. 

In response to the rapid integration of exome sequencing for genetic diagnosis, several professional societies—the International Society for Prenatal Diagnosis, Society for Maternal Fetal Medicine, and Perinatal Quality Foundation—issued a joint statement addressing the clinical use of prenatal diagnostic genome wide sequencing, including exome sequencing. 

Continue to: Guidance at a glance...

The societies' recommendations are summarized as follows: 

• Exome sequencing is best done as a trio analysis, with fetal and both parental samples sequenced and analyzed together. 
• Extensive pretest education, counseling, and informed consent, as well as posttest counseling, are essential. This should include:  

—the types of results to be conveyed (variants that are pathogenic, likely pathogenic, of uncertain significance, likely benign, and benign) 
—the possibility that results will not be obtained or may not be available before the birth of the fetus 
—realistic expectations regarding the likelihood that a significant result will be obtained 
—the timeframe to results 
—the option to include or exclude in the results incidental or secondary findings (such as an unexpected childhood disorder, cancer susceptibility genes, adult-onset disorders) 
—the possibility of uncovering nonpaternity or consanguinity 
—the potential reanalysis of results over time 
—how data are stored, who has access, and for what purpose. 

• Fetal sequencing may be beneficial in the following scenarios: 

—multiple fetal anomalies or a single major anomaly suggestive of a genetic disorder, when the microarray is negative 
—no microarray result is available, but the fetus exhibits a pattern of anomalies strongly suggestive of a single-gene disorder  
—a prior undiagnosed fetus (or child) with anomalies suggestive of a genetic etiology, and with similar anomalies in the current pregnancy, with normal karyotype or microarray. Providers also can consider sequencing samples from both parents prior to preimplantation genetic testing to check for shared carrier status for autosomal recessive mutations, although obtaining exome sequencing from the prior affected fetus (or child) is ideal. 
—history of recurrent stillbirths of unknown etiology, with a recurrent pattern of anomalies in the current pregnancy, with normal karyotype or microarray. 

• Interpretation of results should be done using a multidisciplinary team-based approach, including clinical scientists, geneticists, genetic counselors, and experts in prenatal diagnosis. 
• Where possible and after informed consent, reanalysis of results should be undertaken if a future pregnancy is planned or ongoing, and a significant amount of time has elapsed since the time the result was last reported. 
• Parents should be given a written report of test results. 

Summary

Exome sequencing is increasingly becoming mainstream in postnatal genetic testing, and it is emerging as the newest diagnostic frontier in prenatal genetic testing. However, there are limitations to prenatal exome sequencing, including issues with consent at a vulnerable time for parents, limited information available regarding the phenotype, and results that may not be available before the birth of a fetus. Providers should be familiar with the indications for testing, the possible results, the limitations of prenatal phenotyping, and the implications for future pregnancies. 
 

Prenatal diagnosis of genetic anomalies is important for diagnosing lethal genetic conditions before birth. It can provide information for parents regarding pregnancy options and allow for recurrence risk counseling and the potential use of preimplantation genetic testing in the next pregnancy. For decades, a karyotype was used to analyze amniocentesis and chorionic villus sampling specimens; in recent years, chromosomal microarray analysis provides more information about significant chromosomal abnormalities, including microdeletions and microduplications. However, microarrays also have limitations, as they do not identify base pair changes associated with single-gene disorders.

The advent of next-generation sequencing has substantially reduced the cost of DNA sequencing. Whole genome sequencing (WGS) can sequence the entire genome— both the coding (exonic) and noncoding (intronic) regions—while exome sequencing analyzes only the protein-coding exons, which make up 1% to 2% of the genome and about 85% of the protein-coding genes associated with known human disease. Exome sequencing increasingly is used in cases of suspected genetic disorders when other tests have been unrevealing.

In this Update, we review recent reports of prenatal exome sequencing, including studies exploring the yield in fetuses with structural anomalies; the importance of prenatal phenotyping; the perspectives of parents and health care professionals who were involved in prenatal exome sequencing studies; and a summary of a joint position statement from 3 societies regarding prenatal sequencing.

Prenatal whole exome sequencing has potential utility, with some limitations 

Petrovski S, Aggarwal V, Giordano JL, et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet. 2019;393:758-767. 
 

Lord J, McMullan DJ, Eberhardt RY, et al; for the Prenatal Assessment of Genomes and Exomes Consortium. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet. 2019;393:747-757. 

Exome sequencing has been shown to identify an underlying genetic cause in 25% to 30% of children with an undiagnosed suspected genetic disorder. Two studies recently published in the Lancet sought to determine the incremental diagnostic yield of prenatal whole exome sequencing (WES) in the setting of fetal structural anomalies when karyotype and microarray results were normal. 

Continue to: Details of the studies...

In a prospective cohort study by Petrovski and colleagues, DNA samples from 234 fetuses with a structural anomaly (identified on ultrasonography) and both parents (parent-fetus "trios") were used for analysis. WES identified diagnostic genetic variants in 24 trios (10%). An additional 46 (20%) had variants that indicated pathogenicity but without sufficient evidence to be considered diagnostic. 

The anomalies with the highest frequency of a genetic diagnosis were lymphatic, 24%; skeletal, 24%; central nervous system, 22%; and renal, 16%; while cardiac anomalies had the lowest yield at 5%. 

In another prospective cohort study, known as the Prenatal Assessment of Genomes and Exomes (PAGE), Lord and colleagues sequenced DNA samples from 610 parent-fetus trios, but they restricted sequencing to a predefined list of 1,628 genes. Diagnostic genetic variants were identified in 52 fetuses (8.5%), while 24 (3.9%) had a variant of uncertain significance that was thought to be of potential clinical usefulness. 

Fetuses with multiple anomalies had the highest genetic yield (15.4%), followed by skeletal (15.4%) and cardiac anomalies (11.1%), with the lowest yield in fetuses with isolated increased nuchal translucency (3.2%). 

Diagnostic yield is high, but prenatal utility is limited 

Both studies showed a clinically significant diagnostic yield of 8% to 10% for prenatal exome sequencing in cases of fetal structural anomalies with normal karyotype and microarray testing. While this yield demonstrates the utility of prenatal exome sequencing, it is significantly lower than what has been reported in postnatal studies. One of the reasons for this is the inherent limitation of prenatal phenotyping (discussed below). 

The importance of prenatal phenotyping 

Aarabi M, Sniezek O, Jiang H, et al. Importance of complete phenotyping in prenatal whole exome sequencing. Hum Genet. 2018;137:175-181. 

In postnatal exome sequencing, the physical exam, imaging findings, and laboratory results are components of the phenotype that are used to interpret the sequencing data. Prenatal phenotyping, however, is limited to the use of fetal ultrasonography and, occasionally, the addition of magnetic resonance imaging. Prenatal phenotyping is without the benefit of an exam to detect more subtle anomalies or functional status, such as developmental delay, seizures, or failure to thrive. 

When a structural anomaly is identified on prenatal ultrasonography, it is especially important that detailed imaging be undertaken to detect other anomalies, including more subtle facial features and dysmorphology. 

Value of reanalyzing exome sequencing data 

Aarabi and colleagues conducted a retrospective study of 20 fetuses with structural anomalies and normal karyotype and microarray. They performed trio exome sequencing first using information available only prenatally and then conducted a reanalysis using information available after delivery. 

With prenatal phenotyping only, the investigators identified no pathogenic, or likely pathogenic, variants. On reanalysis of combined prenatal and postnatal findings, however, they identified pathogenic variants in 20% of cases. 

Significance of the findings 

This study highlights both the importance of a careful, detailed fetal ultrasonography study and the possible additional benefit of a postnatal examination (such as an autopsy) in order to yield improved results. In addition, the authors noted that the development of a prenatal phenotype-genotype database would significantly help exome sequencing interpretation in the prenatal setting.

Social impact of WES: Parent and provider perspectives 

Wou K, Weitz T, McCormack C, et al. Parental perceptions of prenatal whole exome sequencing (PPPWES) study. Prenat Diagn. 2018;38:801-811. 

Horn R, Parker M. Health professionals' and researchers' perspectives on prenatal whole genome and exome sequencing: 'We can't shut the door now, the genie's out, we need to refine it.' PLoS One. 2018;13:e0204158. 

As health care providers enter a new era of prenatal genetic testing with exome sequencing, it is crucial to the path forward that we obtain perspectives from the parents and providers who participated in these studies. Notably, in both of the previously discussed Lancet reports, the authors interviewed the participants to discuss the challenges involved and identify strategies for improving future testing. 

Continue to: What parents want...

To ascertain the perceptions of couples who underwent prenatal WES, Wou and colleagues conducted semi-structured interviews with participants from the Fetal Sequencing Study regarding their experience. They interviewed 29 parents from 17 pregnancies, including a mix of those who had pathogenic prenatal results, terminated prior to receiving the results, and had normal results. 
 

Expressed feelings and desires. Parents recalled feelings of anxiety and stress around the time of diagnosis and the need for help with coping while awaiting results. The majority of parents reported that they would like to be told about uncertain results, but that desire decreased as the certainty of results decreased. 

Parents were overall satisfied with the prenatal genetic testing experience, but they added that they would have liked to receive written materials beforehand and a written report of the test results (including negative cases). They also would like to have connected with other families with similar experiences, to have received results sooner, and to have an in-person meeting after telephone disclosure of the results. 

Health professionals articulate complexity of prenatal genomics 

In a qualitative interview study to explore critical issues involved in the clinical practice use of prenatal genomics, Horn and Parker conducted interviews with 20 health care professionals who were involved in the previously described PAGE trial. Patient recruiters, midwives, genetic counselors, research assistants, and laboratory staff were included. 

Interviewees cited numerous challenges involved in their day-to-day work with prenatal whole genome and exome sequencing, including: 

• the complexity of achieving valid parental consent at a time of vulnerability 
• management of parent expectations  
• transmitting and comprehending complex information 
• the usefulness of information 
• the difficulty of a long turnaround time for study results. 

All the interviewees agreed that prenatal exome sequencing studies contribute to knowledge generation and the advancement of technology. 

The authors concluded that an appropriate next step would be the development of appropriate guidelines for good ethical practice that address the concerns encountered in genomics clinical practice.

Societies offer guidance on using genome and exome sequencing 

International Society for Prenatal Diagnosis, Society for Maternal and Fetal Medicine, Perinatal Quality Foundation. Joint Position Statement from the International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality Foundation (PQF) on the use of genome-wide sequencing for fetal diagnosis. Prenat Diagn. 2018;38:6-9. 

In response to the rapid integration of exome sequencing for genetic diagnosis, several professional societies—the International Society for Prenatal Diagnosis, Society for Maternal Fetal Medicine, and Perinatal Quality Foundation—issued a joint statement addressing the clinical use of prenatal diagnostic genome wide sequencing, including exome sequencing. 

Continue to: Guidance at a glance...

The societies' recommendations are summarized as follows: 

• Exome sequencing is best done as a trio analysis, with fetal and both parental samples sequenced and analyzed together. 
• Extensive pretest education, counseling, and informed consent, as well as posttest counseling, are essential. This should include:  

—the types of results to be conveyed (variants that are pathogenic, likely pathogenic, of uncertain significance, likely benign, and benign) 
—the possibility that results will not be obtained or may not be available before the birth of the fetus 
—realistic expectations regarding the likelihood that a significant result will be obtained 
—the timeframe to results 
—the option to include or exclude in the results incidental or secondary findings (such as an unexpected childhood disorder, cancer susceptibility genes, adult-onset disorders) 
—the possibility of uncovering nonpaternity or consanguinity 
—the potential reanalysis of results over time 
—how data are stored, who has access, and for what purpose. 

• Fetal sequencing may be beneficial in the following scenarios: 

—multiple fetal anomalies or a single major anomaly suggestive of a genetic disorder, when the microarray is negative 
—no microarray result is available, but the fetus exhibits a pattern of anomalies strongly suggestive of a single-gene disorder  
—a prior undiagnosed fetus (or child) with anomalies suggestive of a genetic etiology, and with similar anomalies in the current pregnancy, with normal karyotype or microarray. Providers also can consider sequencing samples from both parents prior to preimplantation genetic testing to check for shared carrier status for autosomal recessive mutations, although obtaining exome sequencing from the prior affected fetus (or child) is ideal. 
—history of recurrent stillbirths of unknown etiology, with a recurrent pattern of anomalies in the current pregnancy, with normal karyotype or microarray. 

• Interpretation of results should be done using a multidisciplinary team-based approach, including clinical scientists, geneticists, genetic counselors, and experts in prenatal diagnosis. 
• Where possible and after informed consent, reanalysis of results should be undertaken if a future pregnancy is planned or ongoing, and a significant amount of time has elapsed since the time the result was last reported. 
• Parents should be given a written report of test results. 

Summary

Exome sequencing is increasingly becoming mainstream in postnatal genetic testing, and it is emerging as the newest diagnostic frontier in prenatal genetic testing. However, there are limitations to prenatal exome sequencing, including issues with consent at a vulnerable time for parents, limited information available regarding the phenotype, and results that may not be available before the birth of a fetus. Providers should be familiar with the indications for testing, the possible results, the limitations of prenatal phenotyping, and the implications for future pregnancies. 
 

Prenatal care has long included carrier screening for genetic diseases, such as cystic fibrosis and Tay-Sachs disease. Recently, advances in genetics technologies led to the development of multiplex panels that can be used to test for hundreds of genetic disorders simultaneously, and can be used to assess carrier status for expectant couples or those planning a pregnancy. Although such screening covers many more conditions than those recommended in traditional guidelines, the benefit of expanded carrier screening (ECS) over standard gene-by-gene testing is not clear.

In this Update, I review recent ECS research that can be helpful to those who practice reproductive endocrinology and infertility medicine, maternal–fetal medicine, and general ObGyn. This research considered some of the many complexities of ECS:

• number and type of severe autosomal recessive conditions identified by an ECS panel, or by panethnic screening for 3 common conditions (cystic fibrosis, fragile X syndrome, spinal muscular atrophy)
• whether the disorders covered by ECS panels meet recommended criteria regarding severity, prevalence, and test accuracy
• women’s thoughts and perspectives on ECS
• whether the marketing materials disseminated by commercial providers of ECS are accurate and balanced.

Genetic diseases identified by expanded carrier screening

Haque IS, Lazarin GA, Kang HP, Evans EA, Goldberg JD, Wapner RJ. Modeled fetal risk of genetic diseases identified by expanded carrier screening. JAMA. 2016;316(7):734-742.

Screening during pregnancy to determine if one or both parents are carriers of genetic disorders historically has involved testing for a limited number of conditions, such as cystic fibrosis, hemoglobinopathies, and Tay-Sachs disease. Patients usually are offered testing for 1 or 2 disorders, with test choices primarily based on patient race and ethnicity. Unfortunately, ancestry-based screening may result in inequitable distribution of genetic testing and resources, as it has significant limitations in our increasingly multicultural society, which includes many people of uncertain or mixed race and ethnicity.

Advantages of expanded carrier screening

Several commercial laboratories now offer ECS. Haque and colleagues used data from one of these laboratories and modeled the predicted number of potentially affected fetuses that would be identified with traditional, ethnicity-based screening as compared with ECS. In one of their hypothetical cohorts, of Northern European couples, traditional screening would identify 55 affected fetuses per 100,000 (1 in 1,800), and ECS would identify 159 per 100,000 (almost 3 times more). The numbers identified with ECS varied with race or ethnicity and ranged from 94 per 100,000 (about 1 in 1,000) for Hispanic couples to 392 per 100,000 (about 1 in 250) for Ashkenazi Jewish couples.

In Australia, Archibald and colleagues conducted a similar study, of panethnic screening of 12,000 women for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy.¹ The number of affected fetuses identified was about 1 per 1,000 screened couples--not much different from the ECS number, though comparison is difficult given the likely very different racial and ethnic backgrounds of the 2 cohorts.

Although these data suggest ECS increases detection of genetic disorders, and it seems almost self-evident that more screening is better, there are concerns about ECS.² Traditional carrier screening methods focus on conditions that significantly affect quality of life--owing to cognitive or physical disabilities or required lifelong medical therapies--and that have a fetal, neonatal, or early-childhood onset and well-defined phenotype. In ECS panels, additional conditions may vary significantly in severity or age of onset. Although some genetic variants on ECS panels have a consistent phenotype, the natural history of others is less well understood. Panels often include conditions for which carrier screening of the general population is not recommended by current guidelines--for example, hemochromatosis and factor V Leiden. Moreover, almost by definition, ECS panels include rare conditions for which the natural history may not be well understood, and the carrier frequency as well as the proportion of condition-causing variants that can be detected may be unclear, leaving the residual risk unknown.

Read about the ideal expanded carrier screening panel.

The ideal expanded carrier screening panel

Stevens B, Krstic N, Jones M, Murphy L, Hoskovec J. Finding middle ground in constructing a clinically useful expanded carrier screening panel. Obstet Gynecol. 2017;130(2):279-284.

Both the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) have proposed criteria for including specific disorders on ECS panels.^3,4 These criteria consider disorder characteristics, such as carrier prevalence, which should be at least 1 in 100; severity; early-childhood onset; and complete penetrance. In addition, they consider test characteristics, such as sensitivity, which should be at least 70%.

Details of the study

Stevens and colleagues evaluated the ECS panels offered by 6 commercial laboratories in the United States. They found that only 27% of included conditions met the recommended criteria, and concluded that these panels are putting patients at risk for undue anxiety, and that time and money are being spent on follow-up testing for rare and mild conditions for which the benefits of testing are unclear or unlikely. The potential benefits of the extra screening should be weighed against the significant resulting harms.

Across the 6 ECS panels, 96 conditions met the criteria. As some laboratories allow providers to customize their panels, members of my practice, after reviewing this thought-provoking article, agreed we should create a custom panel that includes only these 96 conditions. Unfortunately, no commercial laboratory includes all 96 conditions, so it is not feasible to create an "ideal" panel at this time.

Arguments favoring ECS include its low cost and the efficiency of screening with multigene panels. In a 2013 study, however, 24% of patients were identified as carriers, and in most cases this finding led to screening for the reproductive partner as well.⁵ If the rate of detection of the disorder is low, the utility of screening with the same panel may be limited, and couples may require more extensive testing, such as gene sequencing, which is far more expensive. These findings and the additional testing also will increase the need for genetic counseling, and may lead to invasive prenatal diagnostic testing with further increases in costs. If counseling and prenatal testing yield improved outcomes--increased detection of important findings--the benefit will justify the higher costs. However, if the increased costs are largely generated chasing down and explaining findings that are not important to patients or providers, the costs may be incurred without benefit.

Read about the pregnant women’s perspectives on ECS.

Pregnant women's perspectives on expanded carrier screening

Propst L, Connor G, Hinton M, Poorvu T, Dungan J. Pregnant women's perspectives on expanded carrier screening [published online February 23, 2018]. J Genet Couns. doi:10.1007/s10897-018-0232-x.

Although several authors have discussed ECS detection rates, less has been reported on how women perceive ECS or how they elect or decline screening. Studies have found that the decision to undergo screening for cystic fibrosis is influenced by factors that include age, sex, ethnicity, socioeconomic status, lack of family history, cost, fear of a blood test, lack of knowledge about the condition, already having children, wanting to avoid having a disabled child, abortion preferences, and feeling pressured by health care providers.^6,7 Propst and colleagues asked women for their perspectives on ECS, on electing or declining screening, and on any anxiety associated with their decision.

Details of the study

Women who declined ECS said they did so because they:

• had no family history
• knew there was a very small chance their partner carried the same condition  
• would not change the course of their pregnancy on the basis of the test results.

Women who elected ECS said they did so because they wanted to:

• know their risk of having a child with a genetic condition
• have all available information about their genetic risks
• be able to make decisions about continuing or terminating their pregnancy.

Women also were asked what they would do if they discovered their fetus had a genetic disorder. About 42% said they were unsure what they would do, 34% said they would continue their pregnancy and prepare for the birth of an affected child, and 24% said they likely would terminate their pregnancy.

The most common reason women gave for declining ECS was that they had no family history. However, ECS is not a good option for women with a positive family history, as they need genetic counseling and specific consideration of their own risks and what testing should be done. The majority of couples who have a child with a genetic disease have no other family history of the disorder. In a study of reproductive carrier screening in Australia, 88% of carriers had no family history.¹ Careful pretest counseling is needed to explain the distinction between, on one hand, genetic counseling and testing for those with a family history of genetic disease and, on the other hand, population screening performed to identify unsuspecting individuals who are healthy carriers of genetic disorders.

Another crucial point about carrier screening is the need to consider how its results will be used, and what options the carrier couple will have. For women who are pregnant when a risk is identified, options include expectant management, with diagnosis after birth, or prenatal diagnosis with termination of an affected fetus, out-adoption of an affected fetus, or expectant management with preparation for caring for an affected child. For women who are not pregnant when they have ECS, additional options include use of a gamete (ovum or sperm) donor to achieve pregnancy, or preimplantation genetic diagnosis with implantation of only unaffected embryos.

Read about the marketing of ECS.

Marketing of expanded carrier screening

Chokoshvili D, Borry P, Vears DF. A systematic analysis of online marketing materials used by providers of expanded carrier screening [published online December 14, 2017]. Genet Med. doi:10.1038/gim.2017.222.

Prenatal carrier screening can be helpful to women and their families, but it is also a high-volume, lucrative business, with many commercial laboratories competing for the growing ECS market. Professional medical societies recommend making all screening candidates aware of the purpose, characteristics, and limitations of the tests, and of the potential significance of their results. As becoming familiar and comfortable with the tests and explaining them to each patient can be time-consuming, and daunting, many busy clinicians have started relying on marketing materials and other information from the commercial laboratories. Therefore analysis of the accuracy of such materials is in order.

Details of the study

Chokoshvili and colleagues performed a systematic analysis of the quality and accuracy of online marketing materials for ECS. They identified 18 providers: 16 commercial laboratories and 2 medical services providers. All described ECS as a useful tool for family planning, and some were very directive in stating that this testing is "one of the most important steps in preparing for parenthood." In their materials, most of the companies cover some limitations, such as residual risk, but none of the commercial laboratories indicate that ECS can overestimate risk (many variants have incomplete penetrance, meaning that some individuals with a positive test result may in fact be asymptomatic throughout their lifetime).

In addition, whereas a large amount of the marketing materials implies the test was developed in line with professional recommendations, none in fact complies with ACOG and ACMG guidance. Finally, though some of the online information provided by laboratories can be helpful, it is important for clinicians to remember that reproductive genetic counseling should be nondirective and balanced. Carrier testing should be based on patient (not provider) values regarding reproductive autonomy.

Summary

ECS increasingly is being adopted into clinical practice. According to ACOG, traditional ethnicity-based screening, panethnic screening (the same limited panel of tests for all patients), and ECS are all acceptable alternatives for prenatal carrier screening.³ For providers who offer ECS, it is important to have a good understanding of each selected test and its limitations. Providers should have a plan for following up patients who have positive test results; this plan may include having genetic counseling and prenatal genetic diagnostic testing in place. Although treatment is available for a few genetic conditions, for the large majority, prenatal screening has not been proved to lead to improved therapeutic options. Providers should try to make sure that patients do not have unrealistic expectations of the outcomes of carrier screening.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Prenatal care has long included carrier screening for genetic diseases, such as cystic fibrosis and Tay-Sachs disease. Recently, advances in genetics technologies led to the development of multiplex panels that can be used to test for hundreds of genetic disorders simultaneously, and can be used to assess carrier status for expectant couples or those planning a pregnancy. Although such screening covers many more conditions than those recommended in traditional guidelines, the benefit of expanded carrier screening (ECS) over standard gene-by-gene testing is not clear.

In this Update, I review recent ECS research that can be helpful to those who practice reproductive endocrinology and infertility medicine, maternal–fetal medicine, and general ObGyn. This research considered some of the many complexities of ECS:

• number and type of severe autosomal recessive conditions identified by an ECS panel, or by panethnic screening for 3 common conditions (cystic fibrosis, fragile X syndrome, spinal muscular atrophy)
• whether the disorders covered by ECS panels meet recommended criteria regarding severity, prevalence, and test accuracy
• women’s thoughts and perspectives on ECS
• whether the marketing materials disseminated by commercial providers of ECS are accurate and balanced.

Genetic diseases identified by expanded carrier screening

Haque IS, Lazarin GA, Kang HP, Evans EA, Goldberg JD, Wapner RJ. Modeled fetal risk of genetic diseases identified by expanded carrier screening. JAMA. 2016;316(7):734-742.

Screening during pregnancy to determine if one or both parents are carriers of genetic disorders historically has involved testing for a limited number of conditions, such as cystic fibrosis, hemoglobinopathies, and Tay-Sachs disease. Patients usually are offered testing for 1 or 2 disorders, with test choices primarily based on patient race and ethnicity. Unfortunately, ancestry-based screening may result in inequitable distribution of genetic testing and resources, as it has significant limitations in our increasingly multicultural society, which includes many people of uncertain or mixed race and ethnicity.

Advantages of expanded carrier screening

Several commercial laboratories now offer ECS. Haque and colleagues used data from one of these laboratories and modeled the predicted number of potentially affected fetuses that would be identified with traditional, ethnicity-based screening as compared with ECS. In one of their hypothetical cohorts, of Northern European couples, traditional screening would identify 55 affected fetuses per 100,000 (1 in 1,800), and ECS would identify 159 per 100,000 (almost 3 times more). The numbers identified with ECS varied with race or ethnicity and ranged from 94 per 100,000 (about 1 in 1,000) for Hispanic couples to 392 per 100,000 (about 1 in 250) for Ashkenazi Jewish couples.

In Australia, Archibald and colleagues conducted a similar study, of panethnic screening of 12,000 women for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy.¹ The number of affected fetuses identified was about 1 per 1,000 screened couples--not much different from the ECS number, though comparison is difficult given the likely very different racial and ethnic backgrounds of the 2 cohorts.

Although these data suggest ECS increases detection of genetic disorders, and it seems almost self-evident that more screening is better, there are concerns about ECS.² Traditional carrier screening methods focus on conditions that significantly affect quality of life--owing to cognitive or physical disabilities or required lifelong medical therapies--and that have a fetal, neonatal, or early-childhood onset and well-defined phenotype. In ECS panels, additional conditions may vary significantly in severity or age of onset. Although some genetic variants on ECS panels have a consistent phenotype, the natural history of others is less well understood. Panels often include conditions for which carrier screening of the general population is not recommended by current guidelines--for example, hemochromatosis and factor V Leiden. Moreover, almost by definition, ECS panels include rare conditions for which the natural history may not be well understood, and the carrier frequency as well as the proportion of condition-causing variants that can be detected may be unclear, leaving the residual risk unknown.

Read about the ideal expanded carrier screening panel.

The ideal expanded carrier screening panel

Stevens B, Krstic N, Jones M, Murphy L, Hoskovec J. Finding middle ground in constructing a clinically useful expanded carrier screening panel. Obstet Gynecol. 2017;130(2):279-284.

Both the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) have proposed criteria for including specific disorders on ECS panels.^3,4 These criteria consider disorder characteristics, such as carrier prevalence, which should be at least 1 in 100; severity; early-childhood onset; and complete penetrance. In addition, they consider test characteristics, such as sensitivity, which should be at least 70%.

Details of the study

Stevens and colleagues evaluated the ECS panels offered by 6 commercial laboratories in the United States. They found that only 27% of included conditions met the recommended criteria, and concluded that these panels are putting patients at risk for undue anxiety, and that time and money are being spent on follow-up testing for rare and mild conditions for which the benefits of testing are unclear or unlikely. The potential benefits of the extra screening should be weighed against the significant resulting harms.

Across the 6 ECS panels, 96 conditions met the criteria. As some laboratories allow providers to customize their panels, members of my practice, after reviewing this thought-provoking article, agreed we should create a custom panel that includes only these 96 conditions. Unfortunately, no commercial laboratory includes all 96 conditions, so it is not feasible to create an "ideal" panel at this time.

Arguments favoring ECS include its low cost and the efficiency of screening with multigene panels. In a 2013 study, however, 24% of patients were identified as carriers, and in most cases this finding led to screening for the reproductive partner as well.⁵ If the rate of detection of the disorder is low, the utility of screening with the same panel may be limited, and couples may require more extensive testing, such as gene sequencing, which is far more expensive. These findings and the additional testing also will increase the need for genetic counseling, and may lead to invasive prenatal diagnostic testing with further increases in costs. If counseling and prenatal testing yield improved outcomes--increased detection of important findings--the benefit will justify the higher costs. However, if the increased costs are largely generated chasing down and explaining findings that are not important to patients or providers, the costs may be incurred without benefit.

Read about the pregnant women’s perspectives on ECS.

Pregnant women's perspectives on expanded carrier screening

Propst L, Connor G, Hinton M, Poorvu T, Dungan J. Pregnant women's perspectives on expanded carrier screening [published online February 23, 2018]. J Genet Couns. doi:10.1007/s10897-018-0232-x.

Although several authors have discussed ECS detection rates, less has been reported on how women perceive ECS or how they elect or decline screening. Studies have found that the decision to undergo screening for cystic fibrosis is influenced by factors that include age, sex, ethnicity, socioeconomic status, lack of family history, cost, fear of a blood test, lack of knowledge about the condition, already having children, wanting to avoid having a disabled child, abortion preferences, and feeling pressured by health care providers.^6,7 Propst and colleagues asked women for their perspectives on ECS, on electing or declining screening, and on any anxiety associated with their decision.

Details of the study

Women who declined ECS said they did so because they:

• had no family history
• knew there was a very small chance their partner carried the same condition  
• would not change the course of their pregnancy on the basis of the test results.

Women who elected ECS said they did so because they wanted to:

• know their risk of having a child with a genetic condition
• have all available information about their genetic risks
• be able to make decisions about continuing or terminating their pregnancy.

Women also were asked what they would do if they discovered their fetus had a genetic disorder. About 42% said they were unsure what they would do, 34% said they would continue their pregnancy and prepare for the birth of an affected child, and 24% said they likely would terminate their pregnancy.

The most common reason women gave for declining ECS was that they had no family history. However, ECS is not a good option for women with a positive family history, as they need genetic counseling and specific consideration of their own risks and what testing should be done. The majority of couples who have a child with a genetic disease have no other family history of the disorder. In a study of reproductive carrier screening in Australia, 88% of carriers had no family history.¹ Careful pretest counseling is needed to explain the distinction between, on one hand, genetic counseling and testing for those with a family history of genetic disease and, on the other hand, population screening performed to identify unsuspecting individuals who are healthy carriers of genetic disorders.

Another crucial point about carrier screening is the need to consider how its results will be used, and what options the carrier couple will have. For women who are pregnant when a risk is identified, options include expectant management, with diagnosis after birth, or prenatal diagnosis with termination of an affected fetus, out-adoption of an affected fetus, or expectant management with preparation for caring for an affected child. For women who are not pregnant when they have ECS, additional options include use of a gamete (ovum or sperm) donor to achieve pregnancy, or preimplantation genetic diagnosis with implantation of only unaffected embryos.

Read about the marketing of ECS.

Marketing of expanded carrier screening

Chokoshvili D, Borry P, Vears DF. A systematic analysis of online marketing materials used by providers of expanded carrier screening [published online December 14, 2017]. Genet Med. doi:10.1038/gim.2017.222.

Prenatal carrier screening can be helpful to women and their families, but it is also a high-volume, lucrative business, with many commercial laboratories competing for the growing ECS market. Professional medical societies recommend making all screening candidates aware of the purpose, characteristics, and limitations of the tests, and of the potential significance of their results. As becoming familiar and comfortable with the tests and explaining them to each patient can be time-consuming, and daunting, many busy clinicians have started relying on marketing materials and other information from the commercial laboratories. Therefore analysis of the accuracy of such materials is in order.

Details of the study

Chokoshvili and colleagues performed a systematic analysis of the quality and accuracy of online marketing materials for ECS. They identified 18 providers: 16 commercial laboratories and 2 medical services providers. All described ECS as a useful tool for family planning, and some were very directive in stating that this testing is "one of the most important steps in preparing for parenthood." In their materials, most of the companies cover some limitations, such as residual risk, but none of the commercial laboratories indicate that ECS can overestimate risk (many variants have incomplete penetrance, meaning that some individuals with a positive test result may in fact be asymptomatic throughout their lifetime).

In addition, whereas a large amount of the marketing materials implies the test was developed in line with professional recommendations, none in fact complies with ACOG and ACMG guidance. Finally, though some of the online information provided by laboratories can be helpful, it is important for clinicians to remember that reproductive genetic counseling should be nondirective and balanced. Carrier testing should be based on patient (not provider) values regarding reproductive autonomy.

Summary

ECS increasingly is being adopted into clinical practice. According to ACOG, traditional ethnicity-based screening, panethnic screening (the same limited panel of tests for all patients), and ECS are all acceptable alternatives for prenatal carrier screening.³ For providers who offer ECS, it is important to have a good understanding of each selected test and its limitations. Providers should have a plan for following up patients who have positive test results; this plan may include having genetic counseling and prenatal genetic diagnostic testing in place. Although treatment is available for a few genetic conditions, for the large majority, prenatal screening has not been proved to lead to improved therapeutic options. Providers should try to make sure that patients do not have unrealistic expectations of the outcomes of carrier screening.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Prenatal care has long included carrier screening for genetic diseases, such as cystic fibrosis and Tay-Sachs disease. Recently, advances in genetics technologies led to the development of multiplex panels that can be used to test for hundreds of genetic disorders simultaneously, and can be used to assess carrier status for expectant couples or those planning a pregnancy. Although such screening covers many more conditions than those recommended in traditional guidelines, the benefit of expanded carrier screening (ECS) over standard gene-by-gene testing is not clear.

In this Update, I review recent ECS research that can be helpful to those who practice reproductive endocrinology and infertility medicine, maternal–fetal medicine, and general ObGyn. This research considered some of the many complexities of ECS:

• number and type of severe autosomal recessive conditions identified by an ECS panel, or by panethnic screening for 3 common conditions (cystic fibrosis, fragile X syndrome, spinal muscular atrophy)
• whether the disorders covered by ECS panels meet recommended criteria regarding severity, prevalence, and test accuracy
• women’s thoughts and perspectives on ECS
• whether the marketing materials disseminated by commercial providers of ECS are accurate and balanced.

Genetic diseases identified by expanded carrier screening

Haque IS, Lazarin GA, Kang HP, Evans EA, Goldberg JD, Wapner RJ. Modeled fetal risk of genetic diseases identified by expanded carrier screening. JAMA. 2016;316(7):734-742.

Screening during pregnancy to determine if one or both parents are carriers of genetic disorders historically has involved testing for a limited number of conditions, such as cystic fibrosis, hemoglobinopathies, and Tay-Sachs disease. Patients usually are offered testing for 1 or 2 disorders, with test choices primarily based on patient race and ethnicity. Unfortunately, ancestry-based screening may result in inequitable distribution of genetic testing and resources, as it has significant limitations in our increasingly multicultural society, which includes many people of uncertain or mixed race and ethnicity.

Advantages of expanded carrier screening

Several commercial laboratories now offer ECS. Haque and colleagues used data from one of these laboratories and modeled the predicted number of potentially affected fetuses that would be identified with traditional, ethnicity-based screening as compared with ECS. In one of their hypothetical cohorts, of Northern European couples, traditional screening would identify 55 affected fetuses per 100,000 (1 in 1,800), and ECS would identify 159 per 100,000 (almost 3 times more). The numbers identified with ECS varied with race or ethnicity and ranged from 94 per 100,000 (about 1 in 1,000) for Hispanic couples to 392 per 100,000 (about 1 in 250) for Ashkenazi Jewish couples.

In Australia, Archibald and colleagues conducted a similar study, of panethnic screening of 12,000 women for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy.¹ The number of affected fetuses identified was about 1 per 1,000 screened couples--not much different from the ECS number, though comparison is difficult given the likely very different racial and ethnic backgrounds of the 2 cohorts.

Although these data suggest ECS increases detection of genetic disorders, and it seems almost self-evident that more screening is better, there are concerns about ECS.² Traditional carrier screening methods focus on conditions that significantly affect quality of life--owing to cognitive or physical disabilities or required lifelong medical therapies--and that have a fetal, neonatal, or early-childhood onset and well-defined phenotype. In ECS panels, additional conditions may vary significantly in severity or age of onset. Although some genetic variants on ECS panels have a consistent phenotype, the natural history of others is less well understood. Panels often include conditions for which carrier screening of the general population is not recommended by current guidelines--for example, hemochromatosis and factor V Leiden. Moreover, almost by definition, ECS panels include rare conditions for which the natural history may not be well understood, and the carrier frequency as well as the proportion of condition-causing variants that can be detected may be unclear, leaving the residual risk unknown.

Read about the ideal expanded carrier screening panel.

The ideal expanded carrier screening panel

Stevens B, Krstic N, Jones M, Murphy L, Hoskovec J. Finding middle ground in constructing a clinically useful expanded carrier screening panel. Obstet Gynecol. 2017;130(2):279-284.

Both the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) have proposed criteria for including specific disorders on ECS panels.^3,4 These criteria consider disorder characteristics, such as carrier prevalence, which should be at least 1 in 100; severity; early-childhood onset; and complete penetrance. In addition, they consider test characteristics, such as sensitivity, which should be at least 70%.

Details of the study

Stevens and colleagues evaluated the ECS panels offered by 6 commercial laboratories in the United States. They found that only 27% of included conditions met the recommended criteria, and concluded that these panels are putting patients at risk for undue anxiety, and that time and money are being spent on follow-up testing for rare and mild conditions for which the benefits of testing are unclear or unlikely. The potential benefits of the extra screening should be weighed against the significant resulting harms.

Across the 6 ECS panels, 96 conditions met the criteria. As some laboratories allow providers to customize their panels, members of my practice, after reviewing this thought-provoking article, agreed we should create a custom panel that includes only these 96 conditions. Unfortunately, no commercial laboratory includes all 96 conditions, so it is not feasible to create an "ideal" panel at this time.

Arguments favoring ECS include its low cost and the efficiency of screening with multigene panels. In a 2013 study, however, 24% of patients were identified as carriers, and in most cases this finding led to screening for the reproductive partner as well.⁵ If the rate of detection of the disorder is low, the utility of screening with the same panel may be limited, and couples may require more extensive testing, such as gene sequencing, which is far more expensive. These findings and the additional testing also will increase the need for genetic counseling, and may lead to invasive prenatal diagnostic testing with further increases in costs. If counseling and prenatal testing yield improved outcomes--increased detection of important findings--the benefit will justify the higher costs. However, if the increased costs are largely generated chasing down and explaining findings that are not important to patients or providers, the costs may be incurred without benefit.

Read about the pregnant women’s perspectives on ECS.

Pregnant women's perspectives on expanded carrier screening

Propst L, Connor G, Hinton M, Poorvu T, Dungan J. Pregnant women's perspectives on expanded carrier screening [published online February 23, 2018]. J Genet Couns. doi:10.1007/s10897-018-0232-x.

Although several authors have discussed ECS detection rates, less has been reported on how women perceive ECS or how they elect or decline screening. Studies have found that the decision to undergo screening for cystic fibrosis is influenced by factors that include age, sex, ethnicity, socioeconomic status, lack of family history, cost, fear of a blood test, lack of knowledge about the condition, already having children, wanting to avoid having a disabled child, abortion preferences, and feeling pressured by health care providers.^6,7 Propst and colleagues asked women for their perspectives on ECS, on electing or declining screening, and on any anxiety associated with their decision.

Details of the study

Women who declined ECS said they did so because they:

• had no family history
• knew there was a very small chance their partner carried the same condition  
• would not change the course of their pregnancy on the basis of the test results.

Women who elected ECS said they did so because they wanted to:

• know their risk of having a child with a genetic condition
• have all available information about their genetic risks
• be able to make decisions about continuing or terminating their pregnancy.

Women also were asked what they would do if they discovered their fetus had a genetic disorder. About 42% said they were unsure what they would do, 34% said they would continue their pregnancy and prepare for the birth of an affected child, and 24% said they likely would terminate their pregnancy.

The most common reason women gave for declining ECS was that they had no family history. However, ECS is not a good option for women with a positive family history, as they need genetic counseling and specific consideration of their own risks and what testing should be done. The majority of couples who have a child with a genetic disease have no other family history of the disorder. In a study of reproductive carrier screening in Australia, 88% of carriers had no family history.¹ Careful pretest counseling is needed to explain the distinction between, on one hand, genetic counseling and testing for those with a family history of genetic disease and, on the other hand, population screening performed to identify unsuspecting individuals who are healthy carriers of genetic disorders.

Another crucial point about carrier screening is the need to consider how its results will be used, and what options the carrier couple will have. For women who are pregnant when a risk is identified, options include expectant management, with diagnosis after birth, or prenatal diagnosis with termination of an affected fetus, out-adoption of an affected fetus, or expectant management with preparation for caring for an affected child. For women who are not pregnant when they have ECS, additional options include use of a gamete (ovum or sperm) donor to achieve pregnancy, or preimplantation genetic diagnosis with implantation of only unaffected embryos.

Read about the marketing of ECS.

Marketing of expanded carrier screening

Chokoshvili D, Borry P, Vears DF. A systematic analysis of online marketing materials used by providers of expanded carrier screening [published online December 14, 2017]. Genet Med. doi:10.1038/gim.2017.222.

Prenatal carrier screening can be helpful to women and their families, but it is also a high-volume, lucrative business, with many commercial laboratories competing for the growing ECS market. Professional medical societies recommend making all screening candidates aware of the purpose, characteristics, and limitations of the tests, and of the potential significance of their results. As becoming familiar and comfortable with the tests and explaining them to each patient can be time-consuming, and daunting, many busy clinicians have started relying on marketing materials and other information from the commercial laboratories. Therefore analysis of the accuracy of such materials is in order.

Details of the study

Chokoshvili and colleagues performed a systematic analysis of the quality and accuracy of online marketing materials for ECS. They identified 18 providers: 16 commercial laboratories and 2 medical services providers. All described ECS as a useful tool for family planning, and some were very directive in stating that this testing is "one of the most important steps in preparing for parenthood." In their materials, most of the companies cover some limitations, such as residual risk, but none of the commercial laboratories indicate that ECS can overestimate risk (many variants have incomplete penetrance, meaning that some individuals with a positive test result may in fact be asymptomatic throughout their lifetime).

In addition, whereas a large amount of the marketing materials implies the test was developed in line with professional recommendations, none in fact complies with ACOG and ACMG guidance. Finally, though some of the online information provided by laboratories can be helpful, it is important for clinicians to remember that reproductive genetic counseling should be nondirective and balanced. Carrier testing should be based on patient (not provider) values regarding reproductive autonomy.

Summary

ECS increasingly is being adopted into clinical practice. According to ACOG, traditional ethnicity-based screening, panethnic screening (the same limited panel of tests for all patients), and ECS are all acceptable alternatives for prenatal carrier screening.³ For providers who offer ECS, it is important to have a good understanding of each selected test and its limitations. Providers should have a plan for following up patients who have positive test results; this plan may include having genetic counseling and prenatal genetic diagnostic testing in place. Although treatment is available for a few genetic conditions, for the large majority, prenatal screening has not been proved to lead to improved therapeutic options. Providers should try to make sure that patients do not have unrealistic expectations of the outcomes of carrier screening.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.