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Diagnostic Whole Exome Sequencing in an Autism Research Population
Whole exome sequencing (WES) is increasingly being used clinically to identify a genetic etiology for autism spectrum disorder (ASD). Studies have shown the diagnostic yield for WES in ASD is around 25% in the clinical laboratory setting, but can be as low as 3.1% for those with isolated ASD. At our ASD focused research center, research WES is offered to all participants who have a confirmed diagnosis of ASD without a known genetic cause, regardless of lack of co-morbid medical conditions or insurance coverage. As clinicians consider what genetic testing is appropriate for their patients and as professional organizations update guidelines around genetic testing for ASD, it will be important to consider results from broader ASD populations beyond those referred for clinical WES.
Objectives:
To assess the diagnostic yield of WES in a broad ASD population from a research center and to describe the genetic findings identified.
Methods:
Participants underwent gold standard diagnostic evaluations for ASD and met both clinical and research criteria for this condition. Informed consent was obtained, and research WES was performed on the trio (proband and both parents) or quad (including a sibling). Qualifying variants were reviewed by a multidisciplinary team of researchers based on guidelines provided by the American College of Medical Genetics, and those variants determined to be likely contributory to the participant’s ASD phenotype were sent for confirmation in a CLIA-approved laboratory.
Results:
In eighty-nine families, six sequence variants were determined by the research team to be likely causal, for an overall diagnostic yield of 6.7%. Four de novo variants in the genes MECP2, HIVEP2, SHANK3 and CHD8 were classified by the CLIA-laboratory as likely pathogenic or pathogenic. A maternally inherited missense variant in the X-linked gene IQSEC2 and a de novo missense variant in the recently described gene MED13 were both classified as variants of uncertain significance (VUS). Including only clinically classified pathogenic and likely pathogenic variants, the diagnostic yield was 4.5%.
Conclusions:
Diagnostic yield in a general ASD research population is much lower than in those referred for clinical testing, likely because cases with ASD referred for clinical WES might be biased towards those with a more severe or complex phenotype. The results of this study are likely more representative of the general ASD population. Challenges highlighted in this study include interpretation of previously unreported missense variants in X-linked genes, as these will frequently be classified as VUS (e.g., IQSEC2). This challenge extends to providing meaningful genetic counseling to mothers who are found to be carriers for a VUS in an X-linked gene. Another challenge is interpretation of, and genetic counseling for, variants identified in newly described genes, such as MED13, where only 13 affected individuals have been described in one publication. On the other hand, with well-studied genes such as MECP2 and SHANK3, a genetic diagnosis provides families the opportunity to connect with robust family communities and participate in clinical trials and research, and allows for thorough recurrence risk counseling.