Identification of a Novel Variant in Myelin Regulatory Growth Factor by Next-Generation Sequencing Led to the Detection of a Clinically Inapparent Congenital Heart Defect in a Patient with a 46,XY Disorder of Sex Development.

In patients with 46,XY disorders of sex development (DSDs), next-generation sequencing (NGS) has high diagnostic efficiency. One contribution to this diagnostic approach is the possibility of applying reverse phenotyping when a variant in a gene associated with multiple organ hits is found. Our aim is to report a case of a patient with 46,XY DSDs in whom the identification of a novel variant in led to the detection of a clinically inapparent congenital heart defect. A full-term newborn presented with ambiguous genitalia, as follows: a 2 cm phallus, penoscrotal hypospadias, partially fused labioscrotal folds, an anogenital distance of 1.2 cm, and non-palpable gonads. The karyotype was 46,XY, serum testosterone and AMH were low, whereas LH and FSH were high, leading to the diagnosis of dysgenetic DSD. Whole exome sequencing identified a novel, heterozygous, nonsense variant in , classified as pathogenic according to the ACMG criteria. encodes a membrane-bound transcriptional factor expressed in several tissues associated with OCUGS syndrome (ophthalmic, cardiac, and urogenital anomalies). In the patient, oriented clinical assessment ruled out ophthalmic defects, but ultrasonography confirmed meso/dextrocardia. We report a novel variant in a patient with 46,XY DSDs, allowing us to identify a clinically inapparent congenital heart defect by reverse phenotyping.