Takafumi Kawano1, Kazuyoshi Hosomichi2, Ituro Inoue3, Ryuichi Shimono4, Shun Onishi1, Kazuhiko Nakame1, Tatsuru Kaji1, Hiroshi Matsufuji5, Satoshi Ieiri6. 1. Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan. 2. Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan. 3. Division of Human Genetics, National Institute of Genetics, Shizuoka, Japan. 4. Department of Pediatric Surgery, Faculty of Medicine, Kagawa University Hospital, Kita, Japan. 5. Department of Pediatric Surgery, St. Luke's International Hospital, Tokyo, Japan. 6. Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan. sieiri@m.kufm.kagoshima-u.ac.jp.
Abstract
PURPOSE: Hirschsprung's disease (HSCR) is a congenital disorder of the enteric nervous system characterized by the absence of ganglion cells in the Auerbach's and Meissner's plexuses. Although about 7% of cases are hereditary, the causal mutations have not been completely characterized. We encountered a novel family with inherited HSCR and screened them for causal mutations. METHODS: A Japanese family of five female patients and six unaffected individuals was subjected to a whole-exome analysis with a next-generation sequencer. RESULTS: After exome sequencing and the annotation of mutations, we identified co-segregated mutations with sequential filtering steps via a standard protocol. Eight mutations were identified: two on chromosome 10 and six on chromosome 11. We used pathogenicity prediction tools such as Genomic Evolutionary Rate Profiling, SIFT, and PolyPhen2 to predict the impact of mutations on the protein activity. S922Y, a novel mutation of RET, was identified as a likely causal mutation. In addition, a mutation of rs2435357T, known as enhancer of RET located in intron 1 of RET, was detected in this family. CONCLUSION: The coexistence of RET mutations in both the exon (S922Y) and intron1 (rs2435357T) indicated a risk of HSCR in this family.
PURPOSE:Hirschsprung's disease (HSCR) is a congenital disorder of the enteric nervous system characterized by the absence of ganglion cells in the Auerbach's and Meissner's plexuses. Although about 7% of cases are hereditary, the causal mutations have not been completely characterized. We encountered a novel family with inherited HSCR and screened them for causal mutations. METHODS: A Japanese family of five female patients and six unaffected individuals was subjected to a whole-exome analysis with a next-generation sequencer. RESULTS: After exome sequencing and the annotation of mutations, we identified co-segregated mutations with sequential filtering steps via a standard protocol. Eight mutations were identified: two on chromosome 10 and six on chromosome 11. We used pathogenicity prediction tools such as Genomic Evolutionary Rate Profiling, SIFT, and PolyPhen2 to predict the impact of mutations on the protein activity. S922Y, a novel mutation of RET, was identified as a likely causal mutation. In addition, a mutation of rs2435357T, known as enhancer of RET located in intron 1 of RET, was detected in this family. CONCLUSION: The coexistence of RET mutations in both the exon (S922Y) and intron1 (rs2435357T) indicated a risk of HSCR in this family.
Entities:
Keywords:
Familial; Genome-wide association study; Hirschsprung’s disease; RET; Short segment
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