Critical exon indexing improves clinical interpretation of copy number variants in neurodevelopmental disorders

E Robert Wassman; Karen S Ho; Diana Bertrand; Kyle W Davis; Megan M Martin; Stephanie Page; Andreas Peiffer; Aparna Prasad; Moises A Serrano; Hope Twede; Rena Vanzo; Stephen W Scherer; Mohammed Uddin; Charles H Hensel

doi:10.1212/NXG.0000000000000378

Critical exon indexing improves clinical interpretation of copy number variants in neurodevelopmental disorders

Neurol Genet. 2019 Dec 6;5(6):e378. doi: 10.1212/NXG.0000000000000378. eCollection 2019 Dec.

Affiliation

¹ Lineagen Inc. (E.R.W., K.S.H., D.B., K.W.D., M.M.M., S.P., A. Peiffer, A. Prasad, M.A.S., H.T., R.V., C.H.H.); Life Designs Ventures (E.R.W.), Park City, UT; Department of Pediatrics (K.S.H., A. Peiffer), University of Utah; The Centre for Applied Genomics (S.W.S., M.U.), The Hospital for Sick Children, Toronto, Ontario, Canada; Program in Genetics and Genome Biology (S.W.S), The Hospital for Sick Children; McLaughlin Centre (S.W.S), University of Toronto, Toronto, Ontario, Canada; and Department of Molecular Genetics (S.W.S), University of Toronto, Toronto, Ontario, Canada.

Abstract

Objective: To evaluate a new tool to aid interpretation of copy number variants (CNVs) in individuals with neurodevelopmental disabilities.

Methods: 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.

Results: 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.

Conclusions: Application of CEI to CNVs in individuals with NDDs can identify genes of potential clinical relevance, aid laboratories in effectively searching the clinical literature, and support the clinical reporting of poorly annotated VUS.