To evaluate a new tool to aid interpretation of copy number variants (CNVs) in individuals with neurodevelopmental disabilities.
Critical exon indexing (CEI) was used to identify genes with critical exons (CEGs) from clinically reported CNVs, which may contribute to neurodevelopmental disorders (NDDs). The 742 pathogenic CNVs and 1,363 variants of unknown significance (VUS) identified by chromosomal microarray analysis in 5,487 individuals with NDDs were subjected to CEI to identify CEGs. CEGs identified in a subsequent random series of VUS were evaluated for relevance to CNV interpretation.
CEI identified a total of 2,492 unique CEGs in pathogenic CNVs and 953 in VUS compared with 259 CEGs in 6,965 CNVs from 873 controls. These differences are highly significant ( p < 0.00001) whether compared as frequency, average, or normalized by CNV size. Twenty-one percent of VUS CEGs were not represented in Online Mendelian Inheritance in Man, highlighting limitations of existing resources for identifying potentially impactful genes within CNVs. CEGs were highly correlated with other indices and known pathways of relevance. Separately, 136 random VUS reports were reevaluated, and 76% of CEGs had not been commented on. In multiple cases, further investigation yielded additional relevant literature aiding interpretation. As one specific example, we discuss GTF2I as a CEG, which likely alters interpretation of several reported duplication VUS in the Williams-Beuren region.
Commercial, Travel funds and consulting fees from sponsor to discuss cases with a client
Genomic mutation load in autism and autism spectrum disorder: use to select therapies and predict prognosis
1) Lineagen, Inc. (sponsor), Chief Medical Officer, 9/2015-9/2017; executive advisor 9/2017-present (unpaid except as noted above in item (3)2) Predictive Laboratories, Co-Director, 8/2019-present
1) Commercial, Novaseek Research, Medical Director, IRB2) Commercial, Genepeeks, Medical Advisor3) Commercial, Stemina, Medical Advisor4) Commercial, NuView Life Sciences, CSO, Medical advisor5) Commercial, Trend Community, Advisor6) Commercial, Phase Genomics, Medical advisor7) Non-profit, TESS Foundation, Board member
1) Lineagen, Inc., salary and stock options2) Predictive Laboratories, salary and stock options
1) Lineagen2) NuView Life Sciences3) Predictive Laboratories
(1) Pending: IDENTIFICATION OF SEIZURE SUSCEPTIBILITY REGION IN WOLF-HIRSCHHORN SYNDROME AND TREATMENT THEREOF (2) Pending: SYSTEMS, DEVICES, AND METHODS FOR CORRELATING GENOTYPIC AND PHENOTYPIC DATA (3) Pending: GENETIC MARKERS ASSOCIATED WITH ASD AND OTHER CHILDHOOD DEVELOPMENTAL DELAY DISORDERS
(1) Clene Nanomedicine, Head of Translational Medicine 2017- present (2) directly related to ms: Lineagen, Principal Scientist, 2011-2017
Reimbursement of travel/lodging/per diem when speaking on Lineagen related activities as an employee of the company.
Lineagen, VP of Clinical & Scientific Affairs Employed 9 total years (started as a genetic counselor)
I am on clinical research projects for Lineagen and have stock options in Lineagen Stock/Stock Options, Medical Equipment & Materials: Lineagen's clinical testing services guide medical treatment
(1) npj Genomic Medicine, Senior Editor, 2015-present (2) G3: Genes, Genomes, Genetics, Senior Editor, 2011- present (3) Journal of Personalized Medicine, Editorial Board, 2010-Present (4) The Open Genomics Journal, Editorial Advisory Board, 2009-present (5) The Hugo Journal, Editorial Board, 2009-present (6) Genome Medicine, Editorial Board, 2008-present (7) Journal of Neurodevelopmental Disorders, Section Editor, 2008-present (8) Autism Research, Editorial Board, 2008-present (9) PathoGenetics, Editorial Board, 2008-present (10) Comparative and Functional Genomics, Editorial Board, 2007-present (11) BMC Medical Genomics, Editorial Board, 2006-present (12) Cytogenetics and Genome Research, Editorial Board, 2005-present
Method of Determining Disease Causality of Genome Mutations (Co-inventor Uddin), i. Serial No. CA 2,927,477, File date: Oct. 17, 2014; Status: Pending ii. Serial No. US 15/092,113, File date: April 6, 2016; Status: Pending
(1) Genome Canada (2) Canadian Institutes of Health Research (3) Canadian Institute for Advanced Research (4) McLaughlin Centre (5) Canada Foundation for Innovation (6) Government of Ontario (7) NIH (8) Qatar National Research Fund (9) Brain Canada
(1) MADR2 Tumour Suppressor Gene, Millipore Corp (2) Lafora's Disease Gene (EPM2a), Athena Diagnostics (3) Novel Lafora's Disease Gene (EPM2b), Athena Diagnostics
Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.
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