Clinical validity assessment of genes frequently tested on intellectual disability/autism sequencing panels.

PURPOSE: Neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and autism spectrum disorder (ASD), exhibit genetic and phenotypic heterogeneity, making them difficult to differentiate without a molecular diagnosis. The Clinical Genome Resource Intellectual Disability/Autism Gene Curation Expert Panel (GCEP) uses systematic curation to distinguish ID/ASD genes that are appropriate for clinical testing (ie, with substantial evidence supporting their relationship to disease) from those that are not. METHODS: Using the Clinical Genome Resource gene-disease validity curation framework, the ID/Autism GCEP classified genes frequently included on clinical ID/ASD testing panels as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship. RESULTS: As of September 2021, 156 gene-disease pairs have been evaluated. Although most (75%) were determined to have definitive roles in NDDs, 22 (14%) genes evaluated had either Limited or Disputed evidence. Such genes are currently not recommended for use in clinical testing owing to the limited ability to assess the effect of identified variants. CONCLUSION: Our understanding of gene-disease relationships evolves over time; new relationships are discovered and previously-held conclusions may be questioned. Without periodic re-examination, inaccurate gene-disease claims may be perpetuated. The ID/Autism GCEP will continue to evaluate these claims to improve diagnosis and clinical care for NDDs.

Prevalence and Penetrance of Rare Pathogenic Variants in Neurodevelopmental Psychiatric Genes in a Health Care System Population.

OBJECTIVE: Autism, schizophrenia, and other clinically distinct neurodevelopmental psychiatric disorders (NPDs) have shared genetic etiologies, including single-gene and multigenic copy number variants (CNVs). Because rare variants are primarily investigated in clinical cohorts, population-based estimates of their prevalence and penetrance are lacking. The authors determined the prevalence, penetrance, and NPD risk of pathogenic single-gene variants in a large health care system population. METHODS: The authors analyzed linked genomic and electronic health record (EHR) data in a subset of 90,595 participants from Geisinger's MyCode Community Health Initiative, known as the DiscovEHR cohort. Loss-of-function pathogenic variants in 94 high-confidence NPD genes were identified through exome sequencing, and NPD penetrance was calculated using preselected EHR diagnosis codes. NPD risk was estimated using a case-control comparison of DiscovEHR participants with and without NPD diagnoses. Results from single-gene variant analyses were also compared with those from 31 previously reported pathogenic NPD CNVs. RESULTS: Pathogenic variants were identified in 0.34% of the DiscovEHR cohort and demonstrated a 34.3% penetrance for NPDs. Similar to CNVs, sequence variants collectively conferred a substantial risk for several NPD diagnoses, including autism, schizophrenia, and bipolar disorder. Significant NPD risk remained after participants with intellectual disability were excluded from the analysis, confirming the association with major psychiatric disorders in individuals without severe cognitive deficits. CONCLUSIONS: Collectively, rare single-gene variants and CNVs were found in >1% of individuals in a large health care system population and play an important contributory role in mental health disorders. Diagnostic genetic testing for pathogenic variants among symptomatic individuals with NPDs could improve clinical outcomes through early intervention and anticipatory therapeutic support.