講演情報
[BO-5]原因不明の胎児構造異常に対するエクソーム解析でのイントロンを含めた評価による診断率向上に向けた試み
○谷口 公介1, 長谷川 冬雪2, 青砥 早希3, 緒方 広子1, 小澤 克典2, 和田 誠司2, 左合 治彦2, 秦 健一郎1,4 (1.国立成育医療研究センター研究所 周産期病態研究部, 2.国立成育医療研究センター 周産期・母性診療センター, 3.国立成育医療研究センター メディカルゲノムセンター, 4.群馬大学 医学系研究科 分子細胞生物学講座)
The diagnostic rate of mendelian disorders using whole exome sequencing (WES) is only 30-40%. We performed trio-WES analysis on 133 cases of fetal structural anomalies from 2011 to 2021. Still, we could not identify the cause in 83 cases (62.4%). For our undiagnosed cases, we took the following three approaches to improve the diagnostic rate: 1) we adopted Loss-of-function observed/expected upper bound fraction (LOEUF) score calculated from the viewpoint of genetic intolerance. Genes with low LOEUF scores can cause haploinsufficiency. In two cases, we identified pathogenic variants of CCDC22 and MED12 that cause X-linked recessive diseases. 2) We generated a list of known disease-causing genes and re-evaluated their variants using spliceAI to narrow down the candidate variants, including introns. As a result, we could identify a pathogenic variant that could cause splice donor loss on the intron of TMEM67 in one case of Meckel-Gruber syndrome. 3) We targeted 2971 genes with low LOEUF scores (less than 0.35) and re-evaluated the variants, including introns, for undiagnosed cases. In this method, we identified a de novo hemizygous pathogenic variant that could cause intron retention on CASK in one case of severe fetal hydrops, polyhydramnios, cerebellar hypoplasia, and intrauterine fetal death. We found a new candidate gene for the cause of fetal hydrops. This study showed that evaluation of variants, including introns, in combination with the LOEUF score is expected to contribute to the improvement of diagnostic rate in WES.