IMPE Abstracts

In patients with 46,XY disorders of sex development (DSD), next-generation sequencing (NGS) analysis leads to an aetiological diagnosis in ~40% of the cases. One contribution of this diagnostic approach is the possibility of applying reverse phenotyping when a variant in a gene associated with multiple organ hits is found. The aim of this work is to report a case of a patient with 46,XY DSD in whom the identification of a novel variant in MYRF led to the detection of a clinically inapparent congenital heart disease. A full-term newborn was referred to our Division at 7 days of life for ambiguous genitalia. There was no relevant family background. Weight and height were within the normal ranges. The patient had a phallus of 2cm (-3.2 SDS) x 1.2 cm (0.1 SDS), penoscrotal hypospadias, partially fused labioscrotal folds, anogenital distance of 1.2cm and non-palpable gonads (External genital score: 4). The karyotype was 46,XY. Serum testosterone (16 ng/dL) and AMH (68 pmol/L) were low, whereas LH (20.2 mUI/mL) and FSH (6.88 mUI/mL) were high for age and chromosomal sex, leading to the presumptive diagnosis of dysgenetic DSD. Whole Exome Sequencing (WES) identified a novel, heterozygous variant in MYRF: NC_000011.9(NM_001127392.3):c.965G>A, NP_001120864.1:p.(Trp322*), which indicated a stop-gain (nonsense) type variant. The variant was classified as likely pathogenic according to the ACMG criteria with a score 9 points (8 points for PVS1 very strong and 1 point for PM2 supporting). MYRF encodes a protein evolutionarily conserved from invertebrates to vertebrates, representing a novel type of membrane-bound transcriptional factor expressed in several tissues. It has been associated with CUDL Syndrome (Cardiac anomalies, Urogenital defects, Diaphragmatic hernia and Lung hypoplasia). In our patient, oriented clinical assessment ruled out diaphragmatic or lung defects, but ultrasonography confirmed meso/dextrocardia. Ocular defects, observed in patients with C-terminal MYRF variants, were absent in this patient carrying a truncating mutation in the N-terminal Pro domain. In conclusion, we report a novel MYRF variant in a patient with 46,XY DSD, which allowed us to identify a clinically inapparent congenital heart defect by reverse phenotyping.