Genetic Microarrays Grow for Neurodevelopmental Diagnosis

MIAMI – Genetic microarrays are driving advances in detection of some important pediatric neurodevelopmental disorders, including fragile X syndrome, microdeletion syndrome, and Klinefelter syndrome.

The discoveries afforded by these microarrays are coming so rapidly that adequate guidance on their use in practice is available largely from experts and specialized sources, said Dr. Nicole R. Tartaglia, a developmental and behavioral pediatrician at Children’s Hospital Colorado, Denver.

In a 2011 review, the American Academy of Neurology evaluated available neurodevelopmental testing and said that microarrays can identify a genetic etiology for 8% of children with global developmental delays or up to 11% if syndromic features are present (Neurology. 2011;77:1629-35). The American Academy of Pediatrics guidelines on Clinical Genetic Evaluation of the Child with Mental Retardation or Developmental Delays and Identification and Evaluation of Children with Autism Spectrum Disorder are several years old and precede the widespread use of microarray analysis.

Microarrays are steering researchers to develop syndrome-specific screening instruments and are likely to lead to the development of targeted therapies for these disorders, further validating the use of genetic testing for developmental delays, Dr. Tartaglia said at a pediatric update sponsored by Miami Children’s Hospital.

Microarray analysis and comprehensive genetic testing often require comprehensive patient and family counseling. Include the uncertainty and scope of genetic testing during your informed consent process, Dr. Tartaglia recommended. "The clinical implications may not be known." In addition, she said, "The lab may request testing follow-up for the parents to identify the implications of the finding if we do detect an abnormality."

Dr. Tartaglia highlighted three specific pediatric neurodevelopmental syndromes where genetic-based screening and potential targeted treatments are particularly promising:

– Fragile X syndrome. Patients with fragile X syndrome can present with an elongated face, prominent ears and among postpubertal males, bigger testicles. "Genetic testing is still important (for diagnosis) because not all will have the facial features," Dr. Tartaglia said.

A differential diagnosis is important because behavioral features overlap with autism spectrum disorder. Hand biting, sensory sensitivities, anxiety, and intellectual disability are examples. The syndrome weakens neural connections and the dendritic spines can become smaller or narrower.

A higher-than-normal repetition of the genetic CGC sequence causes fragile X syndrome, which is the most common inherited disorder of developmental disability, affecting an estimated 1 in 4,000 boys and 1 in 8,000 girls. Normally, there are fewer than 55of these CGC repeats. Emotional problems often arise in patients with 55-200 repeats, Dr. Tartaglia said.

– Microdeletion syndrome. This common genetic disorder is also known as 22q11.2 deletion syndrome and affects approximately 1 in 4,000 children, with only about 15% of cases inherited.

Early speech and motor delays, hypernasal speech caused by palate abnormalities, and intellectual disabilities are characteristic. Approximately 30%-50% of these children will be diagnosed with attention-deficit/hyperactivity disorder. At last count, there are more than 180 clinical features of this syndrome, Dr. Tartaglia said.

Counseling and follow-up are important, as these children often develop multiple medical comorbidities. In addition, they are at increased risk for schizophrenia and other psychotic disorders. "Up to 25% can develop [psychotic disorders] in late adolescence or adulthood."

– Klinefelter syndrome. This disorder affects approximately 1 in 650 males and is the most common sex-chromosome–linked form of aneuploidy. Neurodevelopmental symptoms vary widely, Dr. Tartaglia said. About three-fourths of affected children will have speech and motor delays and about 80% will require special education assistance in school. These boys are often shy and have social difficulties. About one-third are diagnosed with ADHD, mostly the inattentive subtype. "It is important for families to understand the delays." Early recognition of the syndrome can lead to timely initiation of testosterone therapy.

Genetic testing will reveal the boy is born with 47 chromosomes (instead of XY, they feature XXY sex chromosomes). "Even though it’s one of the most common genetic abnormalities, it is underdiagnosed," Dr. Tartaglia said. About 75% remain undiagnosed during their lifetime, perhaps due to the lack of early physical abnormalities that would prompt screening.

"It is important to screen because we know the difficulties later," Dr. Tartaglia said. Testicular dysgenesis during adolescence, mood dysregulation, and osteopenia or osteoporosis can emerge later, for example. Adult men with Klinefelter syndrome also can experience testosterone deficiency, microorchidism, and infertility.

Dr. Tartaglia said she receives research funding from Seaside Therapeutics.

MIAMI – Genetic microarrays are driving advances in detection of some important pediatric neurodevelopmental disorders, including fragile X syndrome, microdeletion syndrome, and Klinefelter syndrome.

The discoveries afforded by these microarrays are coming so rapidly that adequate guidance on their use in practice is available largely from experts and specialized sources, said Dr. Nicole R. Tartaglia, a developmental and behavioral pediatrician at Children’s Hospital Colorado, Denver.

In a 2011 review, the American Academy of Neurology evaluated available neurodevelopmental testing and said that microarrays can identify a genetic etiology for 8% of children with global developmental delays or up to 11% if syndromic features are present (Neurology. 2011;77:1629-35). The American Academy of Pediatrics guidelines on Clinical Genetic Evaluation of the Child with Mental Retardation or Developmental Delays and Identification and Evaluation of Children with Autism Spectrum Disorder are several years old and precede the widespread use of microarray analysis.

Microarrays are steering researchers to develop syndrome-specific screening instruments and are likely to lead to the development of targeted therapies for these disorders, further validating the use of genetic testing for developmental delays, Dr. Tartaglia said at a pediatric update sponsored by Miami Children’s Hospital.

Microarray analysis and comprehensive genetic testing often require comprehensive patient and family counseling. Include the uncertainty and scope of genetic testing during your informed consent process, Dr. Tartaglia recommended. "The clinical implications may not be known." In addition, she said, "The lab may request testing follow-up for the parents to identify the implications of the finding if we do detect an abnormality."

Dr. Tartaglia highlighted three specific pediatric neurodevelopmental syndromes where genetic-based screening and potential targeted treatments are particularly promising:

– Fragile X syndrome. Patients with fragile X syndrome can present with an elongated face, prominent ears and among postpubertal males, bigger testicles. "Genetic testing is still important (for diagnosis) because not all will have the facial features," Dr. Tartaglia said.

A differential diagnosis is important because behavioral features overlap with autism spectrum disorder. Hand biting, sensory sensitivities, anxiety, and intellectual disability are examples. The syndrome weakens neural connections and the dendritic spines can become smaller or narrower.

A higher-than-normal repetition of the genetic CGC sequence causes fragile X syndrome, which is the most common inherited disorder of developmental disability, affecting an estimated 1 in 4,000 boys and 1 in 8,000 girls. Normally, there are fewer than 55of these CGC repeats. Emotional problems often arise in patients with 55-200 repeats, Dr. Tartaglia said.

– Microdeletion syndrome. This common genetic disorder is also known as 22q11.2 deletion syndrome and affects approximately 1 in 4,000 children, with only about 15% of cases inherited.

Early speech and motor delays, hypernasal speech caused by palate abnormalities, and intellectual disabilities are characteristic. Approximately 30%-50% of these children will be diagnosed with attention-deficit/hyperactivity disorder. At last count, there are more than 180 clinical features of this syndrome, Dr. Tartaglia said.

Counseling and follow-up are important, as these children often develop multiple medical comorbidities. In addition, they are at increased risk for schizophrenia and other psychotic disorders. "Up to 25% can develop [psychotic disorders] in late adolescence or adulthood."

– Klinefelter syndrome. This disorder affects approximately 1 in 650 males and is the most common sex-chromosome–linked form of aneuploidy. Neurodevelopmental symptoms vary widely, Dr. Tartaglia said. About three-fourths of affected children will have speech and motor delays and about 80% will require special education assistance in school. These boys are often shy and have social difficulties. About one-third are diagnosed with ADHD, mostly the inattentive subtype. "It is important for families to understand the delays." Early recognition of the syndrome can lead to timely initiation of testosterone therapy.

Genetic testing will reveal the boy is born with 47 chromosomes (instead of XY, they feature XXY sex chromosomes). "Even though it’s one of the most common genetic abnormalities, it is underdiagnosed," Dr. Tartaglia said. About 75% remain undiagnosed during their lifetime, perhaps due to the lack of early physical abnormalities that would prompt screening.

"It is important to screen because we know the difficulties later," Dr. Tartaglia said. Testicular dysgenesis during adolescence, mood dysregulation, and osteopenia or osteoporosis can emerge later, for example. Adult men with Klinefelter syndrome also can experience testosterone deficiency, microorchidism, and infertility.

Dr. Tartaglia said she receives research funding from Seaside Therapeutics.

MIAMI – Genetic microarrays are driving advances in detection of some important pediatric neurodevelopmental disorders, including fragile X syndrome, microdeletion syndrome, and Klinefelter syndrome.

The discoveries afforded by these microarrays are coming so rapidly that adequate guidance on their use in practice is available largely from experts and specialized sources, said Dr. Nicole R. Tartaglia, a developmental and behavioral pediatrician at Children’s Hospital Colorado, Denver.

In a 2011 review, the American Academy of Neurology evaluated available neurodevelopmental testing and said that microarrays can identify a genetic etiology for 8% of children with global developmental delays or up to 11% if syndromic features are present (Neurology. 2011;77:1629-35). The American Academy of Pediatrics guidelines on Clinical Genetic Evaluation of the Child with Mental Retardation or Developmental Delays and Identification and Evaluation of Children with Autism Spectrum Disorder are several years old and precede the widespread use of microarray analysis.

Microarrays are steering researchers to develop syndrome-specific screening instruments and are likely to lead to the development of targeted therapies for these disorders, further validating the use of genetic testing for developmental delays, Dr. Tartaglia said at a pediatric update sponsored by Miami Children’s Hospital.

Microarray analysis and comprehensive genetic testing often require comprehensive patient and family counseling. Include the uncertainty and scope of genetic testing during your informed consent process, Dr. Tartaglia recommended. "The clinical implications may not be known." In addition, she said, "The lab may request testing follow-up for the parents to identify the implications of the finding if we do detect an abnormality."

Dr. Tartaglia highlighted three specific pediatric neurodevelopmental syndromes where genetic-based screening and potential targeted treatments are particularly promising:

– Fragile X syndrome. Patients with fragile X syndrome can present with an elongated face, prominent ears and among postpubertal males, bigger testicles. "Genetic testing is still important (for diagnosis) because not all will have the facial features," Dr. Tartaglia said.

A differential diagnosis is important because behavioral features overlap with autism spectrum disorder. Hand biting, sensory sensitivities, anxiety, and intellectual disability are examples. The syndrome weakens neural connections and the dendritic spines can become smaller or narrower.

A higher-than-normal repetition of the genetic CGC sequence causes fragile X syndrome, which is the most common inherited disorder of developmental disability, affecting an estimated 1 in 4,000 boys and 1 in 8,000 girls. Normally, there are fewer than 55of these CGC repeats. Emotional problems often arise in patients with 55-200 repeats, Dr. Tartaglia said.

– Microdeletion syndrome. This common genetic disorder is also known as 22q11.2 deletion syndrome and affects approximately 1 in 4,000 children, with only about 15% of cases inherited.

Early speech and motor delays, hypernasal speech caused by palate abnormalities, and intellectual disabilities are characteristic. Approximately 30%-50% of these children will be diagnosed with attention-deficit/hyperactivity disorder. At last count, there are more than 180 clinical features of this syndrome, Dr. Tartaglia said.

Counseling and follow-up are important, as these children often develop multiple medical comorbidities. In addition, they are at increased risk for schizophrenia and other psychotic disorders. "Up to 25% can develop [psychotic disorders] in late adolescence or adulthood."

– Klinefelter syndrome. This disorder affects approximately 1 in 650 males and is the most common sex-chromosome–linked form of aneuploidy. Neurodevelopmental symptoms vary widely, Dr. Tartaglia said. About three-fourths of affected children will have speech and motor delays and about 80% will require special education assistance in school. These boys are often shy and have social difficulties. About one-third are diagnosed with ADHD, mostly the inattentive subtype. "It is important for families to understand the delays." Early recognition of the syndrome can lead to timely initiation of testosterone therapy.

Genetic testing will reveal the boy is born with 47 chromosomes (instead of XY, they feature XXY sex chromosomes). "Even though it’s one of the most common genetic abnormalities, it is underdiagnosed," Dr. Tartaglia said. About 75% remain undiagnosed during their lifetime, perhaps due to the lack of early physical abnormalities that would prompt screening.

"It is important to screen because we know the difficulties later," Dr. Tartaglia said. Testicular dysgenesis during adolescence, mood dysregulation, and osteopenia or osteoporosis can emerge later, for example. Adult men with Klinefelter syndrome also can experience testosterone deficiency, microorchidism, and infertility.

Dr. Tartaglia said she receives research funding from Seaside Therapeutics.