Two sisters with cardiac-urogenital syndrome secondary to pathogenic splicing variant in the MYRF gene with unaffected parents: A case of gonadal mosaicism?

BACKGROUND: Cardiac-urogenital syndrome [MIM # 618280] is a newly described very rare syndrome associated with pathogenic variants in the myelin regulatory factor (MYRF) gene that leads to loss of protein function. MYRF is a transcription factor previously associated only with the control of myelin-related gene expression. However, it is also highly expressed in other tissues and associated with various organ anomalies. The clinical picture is primarily dominated by complex congenital cardiac developmental defects, pulmonary hypoplasia, congenital diaphragmatic hernia, and urogenital malformations. CASE PRESENTATION: We present case reports of two siblings of unrelated parents in whom whole-exome sequencing was indicated due to familial occurrence of extensive developmental defects. A new, previously undescribed splicing pathogenic variant c.1388+2T>G in the MYRF gene has been identified in both patients. Both parents are unaffected, tested negative, and have another healthy daughter. The identical de novo event in siblings suggests gonadal mosaicism, which can mimic recessive inheritance. CONCLUSIONS: To our knowledge, this is the first published case of familial cardiac-urogenital syndrome indicating gonadal mosaicism.

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 MYRF 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 MYRF, classified as pathogenic according to the ACMG criteria. MYRF 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 MYRF variant in a patient with 46,XY DSDs, allowing us to identify a clinically inapparent congenital heart defect by reverse phenotyping.

Case Report: De novo variant in myelin regulatory factor in a Chinese child with 46,XY disorder/difference of sex development, cardiac and urogenital anomalies, and short stature.

The myelin regulatory factor (MYRF; MIM# 608329) gene was first identified as a critical transcription factor involved in oligodendrocyte differentiation and central nervous system myelination. With the recent development of exome sequencing, pathogenic variants of MYRF had been considered as the cause of cardiac-urogenital syndrome (CUGS), 46,XY and 46,XX disorders/differences of sex development (DSDs), and nanophthalmos. Herein, we described a 4-year-7-month-old "girl" with ventricular septal defect, atrial septal defect, patent ductus arteriosus, severe pulmonary hypertension, moderate-to-severe tricuspid regurgitation, enlarged coronary sinus, left superior vena cava, and right lung hypoplasia at birth. Later, the patient developed short stature and amblyopia. Further examination revealed a karyotype 46,XY and visible uterus, whereas the presence of gonads were not explored. Laparoscopy revealed dysplasia of testicular gonad. Whole-exome sequencing (WES) was performed and a de novo heterozygous mutation in MYRF was identified, known as c.2817G > A/p. W939* (NM_001127392.3). Therefore, this case report presented multiple clinical manifestations with syndromic symptoms of CUGS, 46,XY DSD, and ocular symptoms. These new data expanded the phenotype of the MYRF variant and may benefit to characterize the phenotypes caused by the variants of this gene.