Prenatal phenotypic delineation of a de novo EYA1 likely pathogenic variant in branchio-oto-renal syndrome.

backgroundBranchio-oto-renal (BOR; MIM 113650) syndrome is primarily linked to pathogenic variants in the EYA1 gene. Although over 200 pathogenic variants of the EYA1 gene have been reported, validation of the pathogenicity of novel variants and the aggregation of prenatal phenotypes are crucial to guide prenatal diagnosis.

methodsThis study analyzed the clinical and genetic data of a fetus presenting with BOR syndrome. A de novo EYA1 gene variant was identified and the functional impact of this variant was validated using minigene splicing assays in vitro. Additionally, a systematic review of prenatal cases with EYA1 variants was conducted to summarize phenotypic frequencies.

resultsPrenatal ultrasound detected left ear anomaly, facial cyst and a persistent right umbilical vein. Genetic testing revealed a novel variant c.640-15G > A in the EYA1 gene. In vitro minigene assays demonstrated an aberrant effect on splicing. According to the American College of Medical Genetics (ACMG) guidelines, this variant was reclassified as likely pathogenic. Systematic literature review indicated that urinary system abnormalities and amniotic fluid anomalies were more prevalent in prenatal cases.

conclusionsThis study adds a novel likely pathogenic variant to the EYA1 variant spectrum in BOR syndrome and suggests that certain prenatal ultrasound phenotypic markers might be strongly associated with EYA1-related diseases.