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. (C) 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Automated summary

Neurodevelopmental disorders such as intellectual disability and autism spectrum disorder exhibit genetic and phenotypic heterogeneity, making it difficult to differentiate them without molecular diagnosis. The Intellectual Disability/Autism Gene Curation Expert Panel uses systematic curation to distinguish genes appropriate for clinical testing from those that are not. Most of the evaluated gene-disease pairs have definitive roles in neurodevelopmental disorders, but some genes have limited or disputed evidence and are currently not recommended for clinical testing. The panel emphasizes the need for periodic re-examination of gene-disease relationships to avoid perpetuating inaccurate claims.