Novel <b><i>VANGL1</i></b> Gene Mutations in 144 Slovakian, Romanian and German Patients with Neural Tube Defects

Abstract

Neural tube defects (NTDs) are a group of congenital malformations of the central nervous system occurring at an average rate of 1 per 1,000 human pregnancies worldwide. Numerous genetic and environmental factors are discussed to be relevant in their etiology. In mice, mutants in >200 genes including the planar cell polarity (PCP) pathway are known to cause NTDs, and recently, heterozygous mutations in the human VANGL1 gene have been described in a small subset of patients with NTDs. We performed a VANGL1 mutation analysis in 144 unrelated individuals with NTDs from Slovakia, Romania and Germany and identified 3 heterozygous missense mutations: c.613G>A (p.Gly205Arg) with an open spina bifida (lumbosacral meningomyelocele), c.557G>A (p.Arg186His) with a closed spina bifida (tethered cord and spinal lipoma) and c.518G>A (p.Arg173His) with an unknown NTD. The c.613G>A mutation was also found in a healthy sibling. None of the mutations were described previously. Findings support that heterozygous VANGL1 mutations represent hypomorphs or conditional mutants predisposing to NTDs and occur at a frequency of approximately 2.1% of open and closed spinal NTDs. The mutations (p.Arg173His, p.Arg186His, p.Gly205Arg) modified conserved regions of the VANGL1 protein and shared similarities with previously described mutants, providing further evidence for the presence of mutational hot spots in these patients.

Expanding the mutational spectrum associated to neural tube defects: Literature revision and description of novel VANGL1 mutations

“…). Mutational reports of VANGL1 were published in four previous studies, two of them were published by our group (Kibar et al, , ; Bartsch et al, ; Doudney et al, ). In a recent additional study, Cai et al () performed a case‐control study of two common VANGL1 polymorphisms, p.Glu347Ala and p.Ala116Thr; thus, we excluded this report because it was not pertinent to the aims of our review.…”

Two Hundred Thirty-Six Children With Developmental Hydrocephalus: Causes and Clinical Consequences

“…Of note, mutations in planar cell polarity genes play a role in the pathogenesis of some neural tube defects in humans 11–13 , while mutations in other planar cell polarity genes give rise to hydrocephalus independent of MM in mice 14 , which is postulated to be the result of impaired development and function of ependymal cilia 15 . The hydrocephalus that accompanies MM may therefore be both a consequence of mechanical obstruction and, in a subset of patients, genetically-based differences in CSF flow.…”

Infantile hydrocephalus: A review of epidemiology, classification and causes

“…Animal models suggest that chronic intrauterine CSF leakage produces the distinctive Chiari II malformation [55, 56], which obstructs CSF flow. However, mutations in planar cell polarity genes such as Fuzzy ( FUZ ) [57], VANGL1 [58] and CELSR1 [59] contribute to NTDs. Other planar cell polarity genes such as CELSR2 [60] and MPDZ [45] can cause hydrocephalus independent of NTDs.…”