TY - JOUR
T1 - Clinical validity assessment of genes frequently tested on intellectual disability/autism sequencing panels
AU - Riggs, Erin Rooney
AU - Bingaman, Taylor I.
AU - Barry, Carrie Ann
AU - Behlmann, Andrea
AU - Bluske, Krista
AU - Bostwick, Bret
AU - Bright, Alison
AU - Chen, Chun An
AU - Clause, Amanda R.
AU - Dharmadhikari, Avinash V.
AU - Ganapathi, Mythily
AU - Gonzaga-Jauregui, Claudia
AU - Grant, Andrew R.
AU - Hughes, Madeline Y.
AU - Kim, Se Rin
AU - Krause, Amanda
AU - Liao, Jun
AU - Lumaka, Aimé
AU - Mah, Michelle
AU - Maloney, Caitlin M.
AU - Mohan, Shruthi
AU - Osei-Owusu, Ikeoluwa A.
AU - Reble, Emma
AU - Rennie, Olivia
AU - Savatt, Juliann M.
AU - Shimelis, Hermela
AU - Siegert, Rebecca K.
AU - Sneddon, Tam P.
AU - Thaxton, Courtney
AU - Toner, Kelly A.
AU - Tran, Kien Trung
AU - Webb, Ryan
AU - Wilcox, Emma H.
AU - Yin, Jiani
AU - Zhuo, Xinming
AU - Znidarsic, Masa
AU - Martin, Christa Lese
AU - Betancur, Catalina
AU - Vorstman, Jacob A.S.
AU - Miller, David T.
AU - Schaaf, Christian P.
N1 - Funding Information:
A.Br. is a shareholder of and employed by Natera. A.Br. has also been an employee of Invitae and Quest Diagnostics commercial laboratories. A.R.C. and K.B. are shareholders of and employed by Illumina, Inc. A.Be. is a shareholder of and is employed by Invitae. B.B. has received research support from Biomarin Pharmaceuticals Inc. He is currently employed by and is a shareholder of Alnylam Pharmaceuticals, Inc. All other authors declare no conflicts of interest.
Funding Information:
This work was supported by the National Human Genome Research Institute of the National Institutes of Health under award number U24HG006834. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2022 American College of Medical Genetics and Genomics
PY - 2022/9
Y1 - 2022/9
N2 - 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.
AB - 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.
KW - Autism
KW - ClinGen
KW - Gene–disease validity
KW - Intellectual disability
KW - Neurodevelopmental disorders
UR - http://www.scopus.com/inward/record.url?scp=85130941604&partnerID=8YFLogxK
U2 - 10.1016/j.gim.2022.05.001
DO - 10.1016/j.gim.2022.05.001
M3 - Article
C2 - 35616647
AN - SCOPUS:85130941604
SN - 1098-3600
VL - 24
SP - 1899
EP - 1908
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 9
ER -