Eur J Med Genet 2019 Apr 18;62(4):229-234. Epub 2018 Jul 18.
Section of Pediatric Surgery, Hospital for Children and Adolescents, University of Helsinki, Finland; Pediatric Liver and Gut Research Group, University of Helsinki, Finland.
The pathogenesis of Hirschsprung disease is complex. Although the RET proto-oncogene is the most frequently affected gene in Hirschsprung disease, rare coding sequence variants explain only a small part of Hirschsprung disease cases. We aimed to assess the genetic background of Hirschsprung disease using a genome-wide association analysis combined with sequencing all RET exons in samples from 105 Hirschsprung disease cases (30 familial and 75 sporadic) and 386 controls. As expected, variants in or near RET showed the strongest overall association with Hirschsprung disease and the most statistically significant association was observed when using a recessive genetic model (rs2435357, NC_000010.10:g.43582056T > C; genotype TT, OR = 17.31, P = 1.462 × 10). Previously published associations in variants in SEMA (rs11766001, NC_000007.13:g.84145202A > C; allele C, OR = 2.268, P = 0.009533) and NRG1 (rs4541858, NC_000008.10:g.32410309A > G; allele G, OR = 1.567, P = 0.015; rs7835688, NC_000008.10:g.32411499G > C; allele C, OR = 1.567, P = 0.015) were also replicated in the genome-wide association analysis. Sequencing revealed a total of 12 exonic RET rare variants. Of these, eight amino acid changing rare variants and two frameshift variants caused or possibly caused Hirschsprung disease. Only a minority of the Hirschsprung disease cases (9/30 familial; 7/75 sporadic) carried one of the rare variants. Excluding the rare variant carriers from the genome-wide association analysis did not appreciably change the association of rs2435357 with Hirschsprung disease. We estimate that approximately two thirds of the sporadic cases may be statistically attributed to the recessive action of the common non-coding RET variants. Thus, even though most cases do not carry rare RET variants, combinations of rare variants and the common non-coding RET variant cause the majority of the cases in our population.