Loss-of-function de novo mutations play an important role in severe human neural tube defects

Abstract

Background Neural tube defects (NTDs) are very common and severe birth defects that are caused by failure of neural tube closure and that have a complex aetiology. Anencephaly and spina bifida are severe NTDs that affect reproductive fitness and suggest a role for de novo mutations (DNMs) in their aetiology. Methods We used whole-exome sequencing in 43 sporadic cases affected with myelomeningocele or anencephaly and their unaffected parents to identify DNMs in their exomes. Results We identified 42 coding DNMs in 25 cases, of which 6 were loss of function (LoF) showing a higher rate of LoF DNM in our cohort compared with control cohorts. Notably, we identified two protein-truncating DNMs in two independent cases in SHROOM3, previously associated with NTDs only in animal models. We have demonstrated a significant enrichment of LoF DNMs in this gene in NTDs compared with the gene specific DNM rate and to the DNM rate estimated from control cohorts. We also identified one nonsense DNM in PAX3 and two potentially causative missense DNMs in GRHL3 and PTPRS. Conclusions Our study demonstrates an important role of LoF DNMs in the development of NTDs and strongly implicates SHROOM3 in its aetiology.

Biology of human melanocyte development, Piebaldism, and Waardenburg syndrome

“… Few human reports of Spina bifida; Synophrys, cleft lip and cryptochidism; Anal Atresia; Choroidal Melanoma; Unilateral renal agenesis; congenital cataracts. In mice, PAX3 mutations induce pigment defects, spina bifida, and heart defects (Truncus arteriosus) …”

Identification of transcripts potentially involved in neural tube closure using RNA sequencing

“…For instance, of four genes with loss-of-function mutations associated with human anencephaly, three were differentially expressed in our screen (Lemay et al, 2015). …”

Genetic and functional analysis of SHROOM1-4 in a Chinese neural tube defect cohort

“…Recently, de novo LoF mutations in SHROOM3 were experimentally associated with the development of NTDs, suggesting that these variants may also contribute to the genetic etiology of severe human NTDs (Lemay et al 2015). However, the genetic contributions of other SHROOM family members to human NTDs have not been previously reported.…”

“…Animal models and human NTD cohort studies have made it clear that SHROOM3 is involved in NTD etiology (Haigo et al 2003; Hildebrand and Soriano 1999; Lemay et al 2015). The importance of SHROOM3 in NTC is beyond dispute, and a recent study identified two protein truncating de novo mutations in SHROOM3 in human NTD patients (Lemay et al 2015).…”

“…The importance of SHROOM3 in NTC is beyond dispute, and a recent study identified two protein truncating de novo mutations in SHROOM3 in human NTD patients (Lemay et al 2015). However, the genetic contributions of other SHROOM family members in NTDs have remained elusive.…”