Identification of a novel variant of the RET proto‑oncogene in a novel family with Hirschsprung’s disease ; 特異な遺伝子形式を持つ家族性ヒルシュスプルング病の遺伝子解析

鹿児島大学 ; 博士(医学) ; Doctor of Philosophy in Medical Science ; 博士論文全文, 最終試験結果の要旨, 論文審査の要旨, 博士論文要旨 ; 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: 2 on chromosome 10 and 6 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 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. ; doctoral thesis