[en] 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.
Disciplines :
Genetics & genetic processes Laboratory medicine & medical technology
Author, co-author :
Riggs, Erin Rooney ; Autism & Developmental Medicine Institute, Geisinger, Danville, PA
Bingaman, Taylor I; Autism & Developmental Medicine Institute, Geisinger, Danville, PA
Barry, Carrie-Ann; Drexel University College of Medicine, Philadelphia, PA
Behlmann, Andrea; Invitae, San Francisco, CA
Bluske, Krista; Illumina, Inc, San Diego, CA
Bostwick, Bret; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
Bright, Alison; Natera, San Carlos, CA
Chen, Chun-An; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
Clause, Amanda R; Illumina, Inc, San Diego, CA
Dharmadhikari, Avinash V; Department of Pathology and Laboratory Medicine, Children's Hospital of Los Angeles, Los Angeles, CA, Keck School of Medicine, University of Southern California, Los Angeles, CA
Ganapathi, Mythily; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY
Gonzaga-Jauregui, Claudia; Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, Mexico
Grant, Andrew R; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, New York Medical College, Valhalla, NY
Hughes, Madeline Y; University of Illinois Chicago, Chicago, IL
Kim, Se Rin; National Human Genome Research Institute, Bethesda, MD
Krause, Amanda; Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
Liao, Jun; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY
Lumaka Zola, Aimé; CHU Liège - Central University Hospital of Liege [BE] > Génétique Humaine
Mah, Michelle; Trillium Health Partners, Mississauga, Ontario, Canada
Maloney, Caitlin M; University of Washington, Seattle, WA
Mohan, Shruthi; University of North Carolina, Chapel Hill, NC
Osei-Owusu, Ikeoluwa A; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA
Reble, Emma; St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
Rennie, Olivia; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
Savatt, Juliann M; Autism & Developmental Medicine Institute, Geisinger, Danville, PA
Shimelis, Hermela; Autism & Developmental Medicine Institute, Geisinger, Danville, PA
Siegert, Rebecca K; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA
Sneddon, Tam P; Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina, Chapel Hill, NC
Thaxton, Courtney; Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina, Chapel Hill, NC
Toner, Kelly A; Drexel University College of Medicine, Philadelphia, PA
Tran, Kien Trung; Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
Webb, Ryan; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA
Wilcox, Emma H; The Warren Alpert Medical School of Brown University, Providence, RI
Yin, Jiani; Department of Neurology, University of California Los Angeles, Los Angeles, CA
Zhuo, Xinming; The Jackson Laboratory for Genomic Medicine, Farmington, CT
Znidarsic, Masa; University Medical Center Ljubljana, Ljubljana, Slovenia
Martin, Christa Lese; Autism & Developmental Medicine Institute, Geisinger, Danville, PA
Betancur, Catalina; Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, Institut de Biologie Paris Seine, Paris, France
Vorstman, Jacob A S; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
Miller, David T; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA
Schaaf, Christian P; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
Lumaka Zola, Aimé ; Centre Hospitalier Universitaire de Liège - CHU ; Université de Liège - ULiège > GIGA > GIGA Cancer - Human Genetics
NHGRI - National Human Genome Research Institute [US-MD] [US-MD] NIH - National Institutes of Health [US-MD] [US-MD]
Funding text :
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.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.
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