Whole-Exome Sequencing Identifies Likely Deleterious Variants in 50 Families with Spina Bifida

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Background: Spina bifida (SB) is the second most common nonlethal malformation (1/1,000 of live births). Several lines of evidence indicate that SB can be of monogenic origin: i) its congenital nature; ii) familial occurrence; iii) it being part of the phenotypic manifestation of known monogenic syndromes; iv) the knowledge that specific master genes govern neural tube morphogenesis; v) and the existence of monogenic mouse models with SB. We hypothesized that whole exome sequencing (WES) enables identification of likely candidate mutations in a list of 170 candidate genes for SB that we generated, and may allow us to identify potential novel genes for SB. Methods: We generated a list of 170 candidate genes of four categories: A) 33 known candidate genes from monogenic mouse SB models, B) 33 known candidate genes from human isolated SB, C) 70 known candidate genes from human syndromic SB, and D) 34 known candidate genes considered as risk factors for human SB. We evaluated WES data of 50 families with SB for likely deleterious variants in the 170 known candidate genes, and for potential novel monogenic causes of SB. Results: Through systematic candidate gene analysis in combination with familybased unbiased evaluation in 50 SB families, we identified 16 likely deleterious variants in 170 SB candidate genes in 14/50 (28%) families: A) 5 variants (5 families) were identified in mouse candidate genes, B) 9 variants (7 families) were identified in human candidate genes for isolated SB, C) 1 variant (1 family) was identified in human syndromic candidate gene, and D) 1 variant was identified in human SB risk candidate gene. In addition, in 11 (22%) of SB families, we have identified mutations in a potential novel gene for SB. Conclusions: In 28% of individuals with SB we identified likely deleterious variants in 170 candidate genes that we generated. Candidate genes that cause SB in mice can be considered as a potential human SB candidate gene. We additionally identified a potential novel gene in 22% of SB families. Funding: Other NIH Support - DK076683

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