Eph and Ephrin Variants in Malaysian Neural Tube Defect Families

Abstract

Neural tube defects (NTDs) are common birth defects with a complex genetic etiology. Mouse genetic models have indicated a number of candidate genes, of which functional mutations in some have been found in human NTDs, usually in a heterozygous state. This study focuses on Ephs-ephrins as candidate genes of interest owing to growing evidence of the role of this gene family during neural tube closure in mouse models. Eph-ephrin genes were analyzed in 31 Malaysian individuals comprising seven individuals with sporadic spina bifida, 13 parents, one twin-sibling and 10 unrelated controls. Whole exome sequencing analysis and bioinformatic analysis were performed to identify variants in 22 known Eph-ephrin genes. We reported that three out of seven spina bifida probands and three out of thirteen family members carried a variant in either EPHA2 (rs147977279), EPHB6 (rs780569137) or EFNB1 (rs772228172). Analysis of public databases shows that these variants are rare. In exome datasets of the probands and parents of the probands with Eph-ephrin variants, the genotypes of spina bifida-related genes were compared to investigate the probability of the gene–gene interaction in relation to environmental risk factors. We report the presence of Eph-ephrin gene variants that are prevalent in a small cohort of spina bifida patients in Malaysian families.

Genome‐wide analysis of spina bifida risk variants in a case–control study from Bangladesh

“…Genome sequencing and exome sequencing allow for the genomic profiling of the small quantities of input DNA obtained from infants, with declining costs allowing more widespread utilization of the technologies (Ross et al, 2017). These methods have been used to identify novel and potential candidate genes for neural tube defects (Lemay et al, 2015; Singh et al, 2017; Spellicy et al, 2018), including spina bifida (Azzarà et al, 2021; Cao et al, 2020; Han et al, 2022; Lemay et al, 2017; Mohd‐Zin et al, 2022; Shah et al, 2016; Wang et al, 2022), and allow for the identification of rare alleles in families (i.e., trios and quads, which include a trio and an unaffected sibling) (Lee & Gleeson, 2020). Our study is a contribution to the larger effort to consolidate data and samples to obtain the larger sample sizes needed to better characterize the genomic architecture underlying the risk of neural tube defects.…”