Genetic Testing in Neurodevelopmental Disorders

Abstract

Neurodevelopmental disorders are the most prevalent chronic medical conditions encountered in pediatric primary care. In addition to identifying appropriate descriptive diagnoses and guiding families to evidence-based treatments and supports, comprehensive care for individuals with neurodevelopmental disorders includes a search for an underlying etiologic diagnosis, primarily through a genetic evaluation. Identification of an underlying genetic etiology can inform prognosis, clarify recurrence risk, shape clinical management, and direct patients and families to condition-specific resources and supports. Here we review the utility of genetic testing in patients with neurodevelopmental disorders and describe the three major testing modalities and their yields – chromosomal microarray, exome sequencing (with/without copy number variant calling), and FMR1 CGG repeat analysis for fragile X syndrome. Given the diagnostic yield of genetic testing and the potential for clinical and personal utility, there is consensus that genetic testing should be offered to all patients with global developmental delay, intellectual disability, and/or autism spectrum disorder. Despite this recommendation, data suggest that a minority of children with autism spectrum disorder and intellectual disability have undergone genetic testing. To address this gap in care, we describe a structured but flexible approach to facilitate integration of genetic testing into clinical practice across pediatric specialties and discuss future considerations for genetic testing in neurodevelopmental disorders to prepare pediatric providers to care for patients with such diagnoses today and tomorrow.

Estrogen Receptor β as a Candidate Regulator of Sex Differences in the Maternal Immune Activation Model of ASD

“…One possibility is that sex chromosome gene effects contribute to ASD etiology. Indeed, mutations in many genes are known to increase the probability of ASD, and some of them, such as FMR1 , MeCP2 , and neuroligins 3 and 4, are on the X-chromosome ( Marco and Skuse, 2006 ; Guy et al, 2011 ; Percy, 2011 ; Zhang et al, 2017 ; Sledziowska et al, 2020 ; Savatt and Myers, 2021 ). While it will not be addressed here, excellent reviews that discuss the chromosomal contributions to sex differences in ASD can be found elsewhere ( Marco and Skuse, 2006 ; Guy et al, 2011 ; Percy, 2011 ; Zhang et al, 2017 ; Sledziowska et al, 2020 ; Savatt and Myers, 2021 ).…”

“…Indeed, mutations in many genes are known to increase the probability of ASD, and some of them, such as FMR1 , MeCP2 , and neuroligins 3 and 4, are on the X-chromosome ( Marco and Skuse, 2006 ; Guy et al, 2011 ; Percy, 2011 ; Zhang et al, 2017 ; Sledziowska et al, 2020 ; Savatt and Myers, 2021 ). While it will not be addressed here, excellent reviews that discuss the chromosomal contributions to sex differences in ASD can be found elsewhere ( Marco and Skuse, 2006 ; Guy et al, 2011 ; Percy, 2011 ; Zhang et al, 2017 ; Sledziowska et al, 2020 ; Savatt and Myers, 2021 ). Another possible explanation for the sex differences observed in ASD is the differential regulation of sex hormones and their receptor-mediated signaling in females and males, leading to differential gene transcription.…”

Mini-Review: Genetic Literacy and Engagement With Genetic Testing for Autism Spectrum Disorder

“…Because there is a clear genetic link to ASD, genetic testing is recommended by both the American College of Medical Genetic and Genomics and the American Academy of Pediatrics following an ASD diagnosis ( Savatt and Myers, 2021 ). ASD is highly heritable, with estimates of twin heritability ranging from 70 to 90%, and recent advances in genetic research have identified over 100 gene or genetic variants associated with risk for ASD ( Johannessen et al, 2016 ; Genovese and Butler, 2020 ; Satterstrom et al, 2020 ; Savatt and Myers, 2021 ). As with many other conditions that have a genetic basis, ASD genetic testing can provide families with an expedited and clearer diagnosis, giving them access to appropriate educational or therapy services.…”

“…Conclusive results from genetic tests can also provide comfort to families affected by ASD. They can ease anxiety and uncertainty, aid medical and legal planning, and even provide a sense of empowerment and reduced negative emotions for the parents ( Savatt and Myers, 2021 ).…”

“…Though genetic testing can provide many psychosocial benefits to families, it does not always yield a conclusive result. The first-tier test for ASD, chromosomal microarray or CMA, yields a diagnostic result in only 15–20% of cases ( Savatt and Myers, 2021 ); in addition, the high frequency of copy number variants associated with ASD risk can produce test results which are not straightforward to interpret. The next logical test option is whole exome sequencing, which can increase the diagnostic yield up to 36% for neurodevelopmental disorders overall, making it the preferred genetic test for many clinicians ( Srivastava et al, 2019 ; Martinez-Granero et al, 2021 ).…”