Abstract
Hirschsprung disease (HSCR, congenital colon aganglionosis) is a relatively common complex genetic condition caused by abnormal development of the enteric nervous system (ENS). Through a recent genome-wide association study conducted on Chinese HSCR patients, we identified a new HSCR contributing locus, neuregulin 1 (NRG1; 8p12), a gene known to be involved in the development of the ENS. As genes in which disease-associated common variants are found are to be considered as candidates for the search of deleterious rare variants (RVs) in the coding sequences, we sequenced the NRG1 exons of 358 sporadic HSCR patients and 333 controls. We identified a total of 13 different heterozygous RVs including 8 non-synonymous (A28G, E134K, V266L, H347Y, P356L, V486M, A511T, P608A) and 3 synonymous amino acid substitutions (P24P, T169T, L483L), a frameshift (E239fsX10), and a c.503-4insT insertion. Functional analysis of the most conserved non-synonymous substitutions, H347Y and P356L, showed uneven intracellular distribution and aberrant expression of the mutant proteins. Except for T169T and V486M, all variants were exclusive to HSCR patients. Overall, there was a statistically significant over-representation of NRG1 RVs in HSCR patients (p = 0.008). We show here that not only common, but also rare variants of the NRG1 gene contribute to HSCR. This strengthens the role of NRG1.
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Acknowledgments
This work was supported by research grants from the Hong Kong Research Grants Council HKU 765407M and 765609M to MGB, HKU778610M to PT and HKU 775710M to ESWN; and from The University of Hong Kong Seed Funding Programme 200911159071 to PT and 200910159040 and 200811159006 to MGB. Support was also obtained from The University of Hong Kong Genomics Strategic Research Theme.
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C. S.-M. Tang, E. S.-W. Ngan, W.-K. Tang and M.-T. So are joint first authors.
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Tang, C.SM., Ngan, E.SW., Tang, WK. et al. Mutations in the NRG1 gene are associated with Hirschsprung disease. Hum Genet 131, 67–76 (2012). https://doi.org/10.1007/s00439-011-1035-4
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DOI: https://doi.org/10.1007/s00439-011-1035-4