Harnessing rare variants in neuropsychiatric and neurodevelopment disorders-a Keystone Symposia report

• Type of Material: Article
• Authors: Jennifer Cable, PhD Science Writer, New York; Ryan Purcell, Emory University; Elise Robinson, Broad Inst MIT & Harvard; Jacob AS Vorstman, Hosp Sick Children; Wendy K Chung, Columbia University; John Constantino, Emory University; Stephan J Sanders, University of California San Francisco; Mustafa Sahin, Harvard Medical School; Ricardo E Dolmetsch, UniQure; Bina M Shah, Project 8p Foundation; Audrey Thurm, NIMH, National Institutes of Health, Bethesda; Christa L Martin, Geisinger; Carrie E Bearden, University of California Los Angeles; Jennifer Mulle, Emory University
• Language: English
• Date: 2021-08-02
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 New York Academy of Sciences.
• Final Published Version (URL): http://dx.doi.org/10.1111/nyas.14658
• Title of Journal or Parent Work: ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
• Volume: 1506
• Issue: 1
• Start Page: 5
• End Page: 17
• Keywords: CHILDREN; intellectual disability; CEREBELLUM; AUTISM SPECTRUM DISORDER; autism heterogeneity; Science & Technology; Multidisciplinary Sciences; 2 deletion; polygenic risk score; autism spectrum disorder; 22Q11.2 DELETION SYNDROME; rare variants; TSC; autism; DUPLICATION; 22q11; TUBEROUS SCLEROSIS COMPLEX; copy number variant; 16P11.2 DELETION; BEHAVIOR; RISK; neurodevelopmental disorders; 3q29 deletion; Science & Technology - Other Topics; SENSITIVE PERIODS; 16p11; schizophrenia; neuropsychiatric disorders

Abstract

Neurodevelopmental neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, have strong genetic risk components, but the underlying mechanisms have proven difficult to decipher. Rare, high-risk variants may offer an opportunity to delineate the biological mechanisms responsible more clearly for more common idiopathic diseases. Indeed, different rare variants can cause the same behavioral phenotype, demonstrating genetic heterogeneity, while the same rare variant can cause different behavioral phenotypes, demonstrating variable expressivity. These observations suggest convergent underlying biological and neurological mechanisms; identification of these mechanisms may ultimately reveal new therapeutic targets. At the 2021 Keystone eSymposium “Neuropsychiatric and Neurodevelopmental Disorders: Harnessing Rare Variants” a panel of experts in the field described significant progress in genomic discovery and human phenotyping and raised several consistent issues, including the need for detailed natural history studies of rare disorders, the challenges in cohort recruitment, and the importance of viewing phenotypes as quantitative traits that are impacted by rare variants.