A compound genetic family with a maternal pathogenic Xp22.2-p21.3 deletion and an inherited 5q15 duplication classified as a VUS: prenatal diagnosis, genetic counseling, and retrospective clinical analysis

Background Prenatal genetic diagnosis using copy number variation sequencing (CNV-seq) frequently identifies variants of uncertain significance (VUS), which complicate genetic counseling. Parental verification studies performed after a fetal copy number variant (CNV) is identified may also reveal incidental parental CNVs unrelated to the indication for testing. We report a family in which parental verification revealed both an inherited 5q15 duplication and a previously undiagnosed maternal Xp22.2-p21.3 deletion. Materials and Methods A 36-year-old pregnant woman (G3P1), whose second pregnancy (2021) had been terminated after a positive non-invasive prenatal testing (NIPT) result without confirmatory diagnostic testing and who was subsequently diagnosed with premature ovarian insufficiency (POI), underwent amniocentesis at 18 weeks of gestation because of advanced maternal age and an adverse obstetric history. Amniotic fluid was analyzed by karyotyping and CNV-seq; parental peripheral blood was analyzed by CNV-seq after a fetal CNV was identified. Results Fetal CNV-seq revealed a 480 kb duplication at 5q15 (chr5:g.94580000_95060000dup) encompassing eight protein-coding genes, which was classified as a VUS. Parental verification showed that the duplication was not detected in the father, whereas the mother carried the same 5q15 duplication. Maternal CNV-seq additionally revealed a 16.65 Mb heterozygous deletion at Xp22.2-p21.3 (chrX:g.12210001_28860000del) encompassing 81 protein-coding genes, including 30 OMIM morbid genes (e.g., ARX , CDKL5 , PHEX , and RS1 ); this deletion was classified as pathogenic. The mother had no overt clinical features of the associated X-linked disorders. The couple elected to continue the pregnancy after counseling, and a term male infant was delivered with no abnormalities identified at birth; longitudinal follow-up is planned. Conclusion This case illustrates two issues in prenatal genomics. First, the 5q15 duplication detected in this family remains a VUS; although its inheritance from an asymptomatic mother is reassuring, it does not establish benignity, and long-term follow-up is required. Second, parental verification performed to trace the origin of a fetal VUS may incidentally identify clinically significant parental CNVs, as occurred in this case with a previously undiagnosed maternal Xp22.2-p21.3 deletion. This incidental finding was relevant to the mother’s own health and reproductive history, provided a plausible explanation for a previous NIPT-positive result, and required separate counseling. We suggest that parental CNV-seq performed after the identification of a fetal VUS be recognized as having the potential to reveal incidental findings and that counseling and consent processes explicitly address this possibility.