中枢神経系異常を有する胎児におけるRNU4-2バリアントの出生前評価

Fetal central nervous system (CNS) anomalies are among the most common congenital malformations, yet the overall prenatal diagnostic yield of current genetic testing remains below 40%. Variants in RNU4-2, a non-coding gene encoding the U4 small nuclear RNA (snRNA), have recently been linked to a novel highly recurrent dominant neurodevelopmental disorder termed ReNU syndrome. While its postnatal phenotype has been well characterized, the contribution of RNU4-2 to fetal CNS anomalies remains unexplored. In this study, we retrospectively analyzed 148 fetuses with CNS anomalies who had non-diagnostic results from karyotyping, chromosomal microarray analysis, and exome sequencing. Targeted Sanger sequencing of RNU4-2 was performed to identify pathogenic variants. Two fetuses harbored the same de novo recurrent variant, n.64_65insT, corresponding to a diagnostic yield of 1.35%. Both cases presented with microcephaly, suggesting that it is a key prenatal feature of ReNU syndrome. Furthermore, molecular confirmation of RNU4-2 resolved a decade-long diagnostic odyssey in one family by excluding an inherited Xp22.13 duplication of uncertain significance as the causal variant. In conclusion, this study provides the first systematic prenatal evaluation of RNU4-2 in fetuses with CNS anomalies, thereby expanding the prenatal phenotypic spectrum of ReNU syndrome. Incorporating RNU4-2 testing into prenatal genetic workflows may enhance diagnostic yield, enable precise genetic counseling, and support informed reproductive decision-making.