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 Maloney; Shruthi 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

doi:10.1016/j.gim.2022.05.001

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

Genet Med. 2022 Sep;24(9):1899-1908. doi: 10.1016/j.gim.2022.05.001. Epub 2022 May 26.

Authors

Erin Rooney Riggs¹, Taylor I Bingaman², Carrie-Ann Barry³, Andrea Behlmann⁴, Krista Bluske⁵, Bret Bostwick⁶, Alison Bright⁷, Chun-An Chen⁶, Amanda R Clause⁵, Avinash V Dharmadhikari⁸, Mythily Ganapathi⁹, Claudia Gonzaga-Jauregui¹⁰, Andrew R Grant¹¹, Madeline Y Hughes¹², Se Rin Kim¹³, Amanda Krause¹⁴, Jun Liao⁹, Aimé Lumaka¹⁵, Michelle Mah¹⁶, Caitlin M Maloney¹⁷, Shruthi Mohan¹⁸, Ikeoluwa A Osei-Owusu¹⁹, Emma Reble²⁰, Olivia Rennie²¹, Juliann M Savatt², Hermela Shimelis², Rebecca K Siegert¹⁹, Tam P Sneddon²², Courtney Thaxton²², Kelly A Toner³, Kien Trung Tran²³, Ryan Webb¹⁹, Emma H Wilcox²⁴, Jiani Yin²⁵, Xinming Zhuo²⁶, Masa Znidarsic²⁷, Christa Lese Martin², Catalina Betancur²⁸, Jacob A S Vorstman²¹, David T Miller²⁹, Christian P Schaaf³⁰

Affiliations

¹ Autism & Developmental Medicine Institute, Geisinger, Danville, PA. Electronic address: eriggs@geisinger.edu.
² Autism & Developmental Medicine Institute, Geisinger, Danville, PA.
³ Drexel University College of Medicine, Philadelphia, PA.
⁴ Invitae, San Francisco, CA.
⁵ Illumina, Inc, San Diego, CA.
⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
⁷ Natera, San Carlos, CA.
⁸ 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.
⁹ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY.
¹⁰ Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, Mexico.
¹¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA; New York Medical College, Valhalla, NY.
¹² University of Illinois Chicago, Chicago, IL.
¹³ National Human Genome Research Institute, Bethesda, MD.
¹⁴ Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
¹⁵ Laboratoire de Génétique Humaine, University of Liège, Liège, Belgium.
¹⁶ Trillium Health Partners, Mississauga, Ontario, Canada.
¹⁷ University of Washington, Seattle, WA.
¹⁸ University of North Carolina, Chapel Hill, NC.
¹⁹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
²⁰ St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.
²¹ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
²² Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina, Chapel Hill, NC.
²³ Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
²⁴ The Warren Alpert Medical School of Brown University, Providence, RI.
²⁵ Department of Neurology, University of California Los Angeles, Los Angeles, CA.
²⁶ The Jackson Laboratory for Genomic Medicine, Farmington, CT.
²⁷ University Medical Center Ljubljana, Ljubljana, Slovenia.
²⁸ Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, Institut de Biologie Paris Seine, Paris, France.
²⁹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA.
³⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany.

Abstract

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.

Keywords: Autism; ClinGen; Gene–disease validity; Intellectual disability; Neurodevelopmental disorders.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autism Spectrum Disorder* / diagnosis
Autism Spectrum Disorder* / genetics
Autistic Disorder* / diagnosis
Autistic Disorder* / genetics
Humans
Intellectual Disability* / diagnosis
Intellectual Disability* / genetics
Neurodevelopmental Disorders* / genetics

Grants and funding

U24 HG006834/HG/NHGRI NIH HHS/United States