Exome analysis in an Estonian multiplex family with neural tube defects—a case report

Introduction Neural tube defects (NTDs) are a group of common and severe congenital birth defects that occur during early embryonic development due to incomplete closure of the neural tube. The genetic architecture of human NTDs, including spina bifida and hydrocephalus, is highly heterogeneous, with multiple genes/loci and both gene-gene and gene-environment interactions involved. Hence, the variation in outcomes also most likely relates to a combination of the severity of different variants in multiple genes and genetic modifiers affecting the biochemical traits. Methods Here, we present a multiple-spouse family with one pedigree lineage where three brothers are affected with NTDs—two lumbar spina bifidas without hydrocephalus and one obstructive hydrocephalus. We sequenced the exomes of three NTD patients and their parents. Results The analysis revealed a heterozygous c.844ins68 variant in CBS , which was carried by all affected individuals and inherited from their mother. All affected individuals had a variable set of additional low frequency deleterious variants in PTK7 , PLCD4 , IL4I1 or RASSF4 as likely causal loci contributing to the disease development. Conclusion This report extends the current knowledge of the genetic background of NTDs and proposes that common and low frequency variants in genes involved mostly in one-carbon metabolism or planar cell polarity (PCP) pathways can act in an additive manner to increase the genetic risk of the disease.