Identification of new candidate genes for spina bifida through exome sequencing.

Purpose: Neural tube defects are a group of birth defects caused by failure of neural tube closure during development. The etiology of NTD, requiring a complex interaction between environmental and genetic factors, is not well understood.

Methods: We performed whole-exome sequencing (WES) in six trios, with a single affected proband with spina bifida, to identify rare/novel variants as potential causes of the NTD.

Results: Our analysis identified four de novo and ten X-linked recessive variants in four of the six probands, all of them in genes previously never implicated in NTD. Among the 14 variants, we ruled out six of them, based on different criteria and pursued the evaluation of eight potential candidates in the following genes: RXRγ, DTX1, COL15A1, ARHGAP36, TKTL1, AMOT, GPR50, and NKRF. The de novo variants where located in the RXRγ, DTX1, and COL15A1 genes while ARHGAP36, TKTL1, AMOT, GPR50, and NKRF carry X-linked recessive variants. This analysis also revealed that four patients presented multiple variants, while we were unable to identify any significant variant in two patients.

Conclusions: Our preliminary conclusion support a major role for the de novo variants with respect to the X-linked recessive variants where the X-linked could represent a contribution to the phenotype in an oligogenic model.