Presentation Information
[BO-5]A new evaluating method for undiagnosed fetal structural anomalies by whole exome sequencing, including introns
○Taniguchi Kosuke1, Fuyuki Hasegawa2, Saki Aoto3, Hiroko Ogata1, Katsusuke Ozawa2, Seiji Wada2, Haruhiko Sago2, Kenichiro Hata1,4 (1.Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan, 2.Center for Maternal-Fetal-Neonatal and Reproductive Medicine, National Center for Child Health and Development,Tokyo, Japan, 3.Medical Genome Center, National Center for Child Health and Development, Tokyo, Japan, 4.Department of Molecular and Cellular Biology, Gumma University, Maebashi, Gunma, Japan)
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.