AB053. NRG1 rare variant effects in Hirschsprung disease patients

Background: Hirschsprung disease (HSCR) is a heterogeneous genetic disorder characterized by absence of ganglion cells along intestines resulting in functional bowel obstruction. NRG1 gene has been implicated in the intestinal ganglionosis. This study aimed to investigate the contribution of NRG1 gene into the HSCR development in Indonesian population.

Methods: We performed Sanger sequencing to find NRG1 variants in 54 HSCR patients.

Results: All patients were sporadic non-syndromic HSCR with 53/54 (98%) and 1/54 (2%) were short-segment and long-segment patients, respectively. NRG1 analysis showed one rare variant, c.397G > C (p.V133L), and three common variants, rs7834206, rs3735774, and rs75155858. The p.V133L was predicted to reside within in a region of high mammalian conservation, overlap with the promoter and enhancer histone marks of relevant tissues such as digestive and smooth muscle tissues and alter AP-4_2, BDP1_disc3, Egr-1_known1, Egr-1_known4, HEN1_2 transcription factor binding motifs. Furthermore, this variant was absent in 92 controls.

Conclusions: This study is the first report of NRG1 rare variant associated with HSCR patients in South-East Asian ancestry and adds insights into the NRG1 effect in the molecular pathogenesis of HSCR.

Keywords: Hirschsprung disease (HSCR); Indonesia; NRG1 rare variant; transcription factor binding motif