Identification of 22q13 genes most likely to contribute to Phelan McDermid syndrome

• Type of Material: Article
• Authors: Andrew R. Mitz, National Institute of Mental Health; Travis J. Philyaw, University of Utah; Luigi Boccuto, Greenwood Genetic Center; Aleksandr Shcheglovitov, University of Utah; Sara M. Sarasua, Care Coordination Institute; Walter E. Kaufmann, Emory University; Audrey Thurm, National Institute of Mental Health
• Language: English
• Date: 2018-01-22
• Publisher: Springer Nature [academic journals on nature.com]: Hybrid Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The author.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41431-017-0042-x
• Title of Journal or Parent Work: European Journal of Human Genetics
• ISSN: 1018-4813
• Volume: 26
• Issue: 3
• Start Page: 293
• End Page: 302
• Grant/Funding Information: This research was supported (in part) by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (Annual Report numbers: ZIA MH002868 and ZIAMH002886), by a Seed Grant from the Simons Center for the Social Brain, at the Genes of Phelan McDermid syndrome 299 Massachusetts Institute of Technology, and support from the Simons Foundation to WEK, and by the Slifka/Ritvo Innovation in Autism Award and Whitehall (2015-08-86), Brain Research Foundation (BRFSG-2016-08) and Brain and Behaviour Foundation (25456) Grants to AS.
• Keywords: CEREBELLAR; ACTIVATED PROTEIN-KINASE; SHANK3 GENE; BRAIN; DELETION SYNDROME; Biochemistry & Molecular Biology; Life Sciences & Biomedicine; Genetics & Heredity; SCAFFOLD PROTEINS; AUTISM SPECTRUM DISORDER; SCHIZOPHRENIA; CONTROLLED-TRIAL; EXPRESSION; Science & Technology
• Research Categories: Health Sciences, Mental Health; Biology, Genetics

Abstract

Chromosome 22q13.3 deletion (Phelan McDermid) syndrome (PMS) is a rare genetic neurodevelopmental disorder resulting from deletions or other genetic variants on distal 22q. Pathological variants of the SHANK3 gene have been identified, but terminal chromosomal deletions including SHANK3 are most common. Terminal deletions disrupt up to 108 protein-coding genes. The impact of these losses is highly variable and includes both significantly impairing neurodevelopmental and somatic manifestations. The current review combines two metrics, prevalence of gene loss and predicted loss pathogenicity, to identify likely contributors to phenotypic expression. These genes are grouped according to function as follows: molecular signaling at glutamate synapses, phenotypes involving neuropsychiatric disorders, involvement in multicellular organization, cerebellar development and functioning, and mitochondrial. The likely most impactful genes are reviewed to provide information for future clinical and translational investigations.