RET somatic mutations are underrecognized in Hirschsprung disease.
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ABSTRACT: Purpose
We aimed to determine the frequency of RET mosaicism in Hirschsprung disease (HSCR), test whether it has been underestimated, and to assess its contribution to HSCR risk.Methods
Targeted exome sequencing (n?=?83) and RET single-gene screening (n?=?69) were performed. Amplicon-based deep sequencing was applied on multiple tissue samples. TA cloning and sequencing were conducted for validation.Results
We identified eight de novo mutations in 152 patients (5.2%), of which six were pathogenic mosaic mutations. Two of these patients were somatic mosaics, with mutations detected in blood, colon, and saliva (mutant allele frequency: 35-44%). In addition, germ-line mosaicism was identified in four clinically unaffected subjects, each with an affected child, in multiple tissues (mutant allele frequency: 1-28%).Conclusion
Somatic mutations of the RET gene are underrecognized in HSCR. Molecular investigation of the parents of patients with seemingly sporadic mutations is essential to determine recurrence risk in these families.
SUBMITTER: Jiang Q
PROVIDER: S-EPMC7814876 | biostudies-literature | 2018 Jul
REPOSITORIES: biostudies-literature
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Project description:Background RET and Semaphorin 3 (SEMA3) common variants have been associated with Hirschsprung disease (HSCR), but their genetic interactions for development of HSCR is not established yet. To determine the joint effects of RET gene, rs2435357, and SEMA3 gene with three markers; rs1583147, rs12707682, and rs11766001 polymorphisms in Indonesian HSCR patients. Methods Sixty HSCR patients and 115 non-HSCR controls were included in this study. Four genetic markers of the RET and SEMA3 were examined in 175 DNAs using TaqMan Genotyping assay. Case-control analysis and transmission disequilibrium test (TDT) were used to determine an association between four genetic markers and HSCR. We used a P value of <0.013 for a significant association. Results There was a strong association between RET rs2435357 marker and HSCR either by case-control analysis (OR =4.46, P=2.5×10?8) or TDT (P=4.2×10?6), but not SEMA3 rs1583147 (OR =1.9, P=0.023 and P=0.11, respectively) and rs12707682 (OR =1.5, P=0.06 and P=0.041, respectively). Two locus analyses of variants revealed that RET rs2435357 (TT), in combination with SEMA3 rs1583147 (CT) or rs12707682 (CC), were associated with the augmented disease risks of HSCR (OR =2.88, P=0.016 and OR =19.9, P=0.005, respectively) compared with a single variant of SEMA3 rs1583147 or rs12707682. Moreover, the SEMA3 rs11766001 frequencies in HSCR patients and non-HSCR subjects were 1.7% and 0.8% (P=0.48), respectively. Conclusions The genetic effects of SEMA3 genotypes are epistatic to RET. The rarity of SEMA3 rs11766001 in Indonesia could be explained by the founder effect.
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