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

BackgroundCardiac-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 PresentationWe 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. ConclusionsTo our knowledge, this is the first published case of familial cardiac-urogenital syndrome indicating gonadal mosaicism.

Automated summary

Cardiac-urogenital syndrome is a rare syndrome associated with pathogenic variants in the MYRF gene, leading to loss of protein function. It is characterized by complex congenital cardiac defects, pulmonary hypoplasia, diaphragmatic hernia, and urogenital malformations. We report a case of two siblings with extensive developmental defects, who were found to have a novel splicing pathogenic variant in the MYRF gene. The presence of the identical de novo event in siblings suggests gonadal mosaicism, which mimics recessive inheritance. This is the first published case indicating gonadal mosaicism in familial cardiac-urogenital syndrome.