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

Erin Rooney Riggs, Taylor I. Bingaman, Carrie Ann Barry, Andrea Behlmann, Krista Bluske, Bret Bostwick, Alison Bright, Chun An Chen, Amanda R. Clause, Avinash V. Dharmadhikari, Mythily Ganapathi, Claudia Gonzaga-Jauregui, Andrew R. Grant, Madeline Y. Hughes, Se Rin Kim, Amanda Krause, Jun Liao, Aimé Lumaka, Michelle Mah, Caitlin M. MaloneyShruthi Mohan, Ikeoluwa A. Osei-Owusu, Emma Reble, Olivia Rennie, Juliann M. Savatt, Hermela Shimelis, Rebecca K. Siegert, Tam P. Sneddon, Courtney Thaxton, Kelly A. Toner, Kien Trung Tran, Ryan Webb, Emma H. Wilcox, Jiani Yin, Xinming Zhuo, Masa Znidarsic, Christa Lese Martin, Catalina Betancur, Jacob A.S. Vorstman, David T. Miller, Christian P. Schaaf

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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.

Original languageEnglish
Pages (from-to)1899-1908
Number of pages10
JournalGenetics in Medicine
Issue number9
StatePublished - Sep 2022
Externally publishedYes


  • Autism
  • ClinGen
  • Gene–disease validity
  • Intellectual disability
  • Neurodevelopmental disorders


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