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

Researchers reviewed genes commonly tested when children are screened for intellectual disability or autism. They found that while most genes (75%) have strong evidence linking them to these conditions, about 14% of genes being tested don't have enough evidence to reliably interpret results. This means some genetic tests might give unclear or potentially misleading information to families.

This study by the Clinical Genome Resource Intellectual Disability/Autism Gene Curation Expert Panel systematically evaluated 156 gene-disease pairs commonly included on clinical ID/autism testing panels. The panel used standardized criteria to classify genes based on evidence strength supporting their relationship to neurodevelopmental disorders. Results showed that 75% of evaluated genes had definitive roles in NDDs, while 14% had limited or disputed evidence. The findings highlight that 22 genes currently used in clinical testing lack sufficient evidence to reliably interpret identified variants, potentially affecting diagnostic accuracy and clinical decision-making for individuals with intellectual disability and autism spectrum disorders.

Clinical genetic testing panels for ID/autism should be regularly reviewed to ensure included genes have sufficient evidence. Clinicians should be aware that approximately 14% of commonly tested genes may provide uncertain results, potentially affecting diagnostic confidence and family counseling.

Study does not provide details on methodology for gene selection or specific criteria used for evidence classification. No information on sample sizes or patient populations studied. The review is limited to genes as of September 2021.

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. 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. 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. 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.