Case Report: De novo USP9X missense mutation in a male fetus with pulmonary atresia and ventricular septal defect: expanding the genotype-phenotype spectrum of USP9X-related disorders

Background Pathogenic variants in the X-linked USP9X gene, which evades X-chromosome inactivation, have been predominantly linked to neurodevelopmental disorders (NDDs). Accumulating evidence has linked USP9X dysfunction to congenital heart disease (CHD), yet the specific genotype-phenotype correlations in this context remain poorly characterized. Pulmonary atresia with ventricular septal defect (PA/VSD) represents a severe and complex form of congenital heart disease (CHD), characterized by heterogeneous etiological mechanisms. Case presentation A 34-year-old G2P1L1 woman was referred at 22 weeks of gestation for prenatal echocardiography due to suspected fetal cardiac anomaly. Echocardiographic evaluation identified a male fetus with PA/VSD. Following detailed counseling, the couple elected to terminate the pregnancy due to the poor prognosis and opted for subsequent genetic testing. Trio whole-exome sequencing (WES) identified a de novo hemizygous missense variant in USP9X (NM₀01039590. 3: c. 5186A G; p. His1729Arg; rs2147230302) in the male fetus. This variant is categorized as “Likely Pathogenic” in ClinVar for female-restricted syndromic neurodevelopmental disorders (NDDs), yet it has not been previously linked to congenital heart diseases (CHDs), specifically PA/VSD. The p. His1729Arg substitution impacts a conserved residue within the structurally critical zinc-finger domain of the USP9X protein. Comprehensive genetic screening failed to identify additional pathogenic variants that could explain the observed phenotype. Conclusion This case represents the first report establishing a link between the de novo p. His1729Arg variant in USP9X and the CHD phenotype of PA/VSD in a male fetus. This finding broadens the known phenotypic spectrum of this likely pathogenic USP9X variant, underscoring its pleiotropic effects and implicating the gene in critical cardiac developmental pathways. Routine cardiac assessment is recommended for individuals harboring pathogenic USP9X variants.