先天性横隔膜ヘルニアの全エクソームシーケンシングによる新規候補遺伝子の発見

Congenital diaphragmatic hernia (CDH) is a developmental anomaly associated with high mortality and morbidity, primarily attributed to accompanying pulmonary hypoplasia. Genetic factors are crucial in the etiology and pathogenesis of CDH, with various copy number variations (CNVs) and gene sequence variants implicated in this malformation. Previous studies have underscored the importance of retinoic acid (RA) signaling pathways and related genes. Nonetheless, the complexity of diaphragmatic development involving cell migration, cytoskeleton organization, and myogenesis suggests that candidate CDH genes extend beyond the RA pathway. To explore novel candidate gene variants and their roles in CDH, we performed whole exome sequencing (WES) in CDH-affected fetuses.

Following the evaluation of chromosome and array-CGH analyses, 17 CDH cases with normal results in our cohort were subjected to WES. Trio-WES was conducted on eight fetuses, while solo-WES was applied to the remaining nine cases. The identified variants were validated and subjected to segregation analysis via Sanger sequencing.

Bioinformatic analysis revealed novel potentially pathogenic variants not only in six genes previously known to be associated with CDH (NR2F2, ZFPM2, ARID1A, CREBBP, PLAT, and RARB) but also in nine additional genes (COL11A1, NEIL2, PCSK5, RBM8A, STAB2, SETD5, TAF4, ZBTB38, and ZNF423) that, based on their functions, database entries, and literature, may be considered candidate genes for CDH.

Our findings reinforce that no single gene or variant is responsible for the majority of CDH cases, and also demonstrated the effectiveness of WES in identifying novel candidate genes and variants that contribute to CDH etiology.