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

• 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
• Journal Title: ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
• Volume: Volume 1506, Number 1
• Publisher: WILEY | 2021-08-02, Pages 5-17
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1111/nyas.14658
• Subjects: Biology, Cell
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; autism; autism heterogeneity; autism spectrum disorder; copy number variant; intellectual disability; neurodevelopmental disorders; neuropsychiatric disorders; polygenic risk score; rare variants; schizophrenia; 3q29 deletion; TSC; 16p11; 2 deletion; 22q11; TUBEROUS SCLEROSIS COMPLEX; AUTISM SPECTRUM DISORDER; 22Q11.2 DELETION SYNDROME; SENSITIVE PERIODS; 16P11.2 DELETION; CHILDREN; BEHAVIOR; RISK; DUPLICATION; CEREBELLUM

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.