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

• Published in: Genetics in medicine Vol. 24; no. 9; pp. 1899 - 1908
• Main Authors: Riggs, Erin Rooney, Bingaman, Taylor I., Barry, Carrie-Ann, Behlmann, Andrea, Bluske, Krista, Bostwick, Bret, Bright, Alison, Chen, Chun-An, Clause, Amanda R., Dharmadhikari, Avinash V., Ganapathi, Mythily, Gonzaga-Jauregui, Claudia, Grant, Andrew R., Hughes, Madeline Y., Kim, Se Rin, Krause, Amanda, Liao, Jun, Lumaka, Aimé, Mah, Michelle, Maloney, Caitlin M., Mohan, Shruthi, Osei-Owusu, Ikeoluwa A., Reble, Emma, Rennie, Olivia, Savatt, Juliann M., Shimelis, Hermela, Siegert, Rebecca K., Sneddon, Tam P., Thaxton, Courtney, Toner, Kelly A., Tran, Kien Trung, Webb, Ryan, Wilcox, Emma H., Yin, Jiani, Zhuo, Xinming, Znidarsic, Masa, Martin, Christa Lese, Betancur, Catalina, Vorstman, Jacob A.S., Miller, David T., Schaaf, Christian P.
• Format: Journal Article Web Resource
• Language: English
• Published: United States Elsevier Inc 01.09.2022; Nature Publishing Group; Elsevier B.V
• Subjects: Autism; Autism Spectrum Disorder - diagnosis; Autism Spectrum Disorder - genetics; Autistic Disorder - diagnosis; Autistic Disorder - genetics; ClinGen; Genetics; Genetics & genetic processes; Genetics (clinical); Gene–disease validity; Génétique & processus génétiques; Human genetics; Human health sciences; Humans; Intellectual disability; Intellectual Disability - diagnosis; Intellectual Disability - genetics; Laboratory medicine & medical technology; Life Sciences; Médecine de laboratoire & technologie médicale; Neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Sciences de la santé humaine; Sciences du vivant; Autism; Gene–disease validity; Intellectual disability; Neurodevelopmental disorders; ClinGen
• ISSN: 1098-3600; 1530-0366; 1530-0366
• DOI: 10.1016/j.gim.2022.05.001

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.