NRG1 variant effects in patients with Hirschsprung disease

Gunadi, Nova Yuli Prasetyo Budi, Raman Sethi, Aditya Rifqi Fauzi, Alvin Santoso Kalim,
Taufik Indrawan, Kristy Iskandar, Akhmad Makhmudi, Indra Adrianto and Lai Poh San

Background: Hirschsprung disease (HSCR) is a heterogeneous genetic disorder characterized by absence of ganglion
cells along the intestines resulting in functional bowel obstruction. Mutations in neuregulin 1 (NRG1) gene have been
implicated in some cases of intestinal aganglionosis. This study aims to investigate the contribution of the NRG1 gene
to HSCR development in an Indonesian population.
Methods: We analyzed the entire coding region of the NRG1 gene in 54 histopathologically diagnosed HSCR patients.
Results: All patients were sporadic non-syndromic HSCR with 53/54 (98%) short-segment and 1/54 (2%) long-segment
patients. NRG1 gene analysis identified one rare variant, c.397G > C (p.V133 L), and three common variants, rs7834206,
rs3735774, and rs75155858. The p.V133 L variant was predicted to reside within a region of high mammalian
conservation, overlapping with the promoter and enhancer histone marks of relevant tissues such as digestive
and smooth muscle tissues and potentially altering the AP-4_2, BDP1_disc3, Egr-1_known1, Egr-1_known4, HEN1_2
transcription factor binding motifs. This p.V133 L variant was absent in 92 non-HSCR controls. Furthermore, the rs7834206
polymorphism was associated with HSCR by case–control analysis (p = 0.037).
Conclusions: This study is the first report of a NRG1 rare variant associated with HSCR patients of South-East Asian
ancestry and provides further insights into the contribution of NRG1 in the molecular genetic pathogenesis of HSCR.[embeddoc url=”http://bedahfkkmk.ugm.ac.id/wp-content/uploads/sites/1602/2021/11/10.1186@s12887-018-1265-x.pdf” download=”all” viewer=”google”]