MYRF – cardiac-urogenital syndrome

MYRF encodes a membrane-associated transcription factor essential for oligodendrocyte differentiation and central nervous system myelination. Recent sequencing studies have expanded its role to a multisystem syndrome characterized by congenital heart defects and urogenital anomalies, now termed cardiac-urogenital syndrome (MONDO:0032653). The gene exhibits constraint for loss-of-function variation in population databases, consistent with dosage sensitivity.

A de novo heterozygous nonsense variant, c.2817G>A (p.Gln838Ter), was identified by whole-exome sequencing in a 4-year-7-month-old individual presenting with ventricular septal defect, atrial septal defect, patent ductus arteriosus, pulmonary hypertension, right lung hypoplasia, short stature, amblyopia and 46,XY DSD features (PMID:36467480). This single case underscores the syndromic overlap of cardiac and urogenital anomalies in MYRF haploinsufficiency.

In a cohort of 362 congenital diaphragmatic hernia trios, four unrelated probands harbored de novo MYRF loss-of-function variants (1 LGD, 3 deleterious missense) with P = 5.3×10⁻⁸, and eight additional carriers were ascertained from literature review. All individuals exhibited diaphragmatic hernia with concomitant congenital heart disease and genitourinary defects, delineating a novel MYRF-related syndrome (PMID:30532227).

The spectrum of pathogenic variants includes nonsense, frameshift, splice-site and deleterious missense changes clustering in the ICA autoproteolysis and DNA-binding domains. Recurrent truncating alleles such as p.Gln838Ter and p.Gln596Ter lead to premature termination and predicted loss of transcriptional activity.

Functional assays demonstrate that ICA domain mutations (p.Val679Ala, p.Arg695His) abolish MYRF autoproteolysis and nuclear translocation, leading to complete loss of transcriptional activity consistent with haploinsufficiency (PMID:31964908). DNA-binding domain variants (p.Phe387Ser, p.Gln403His, p.Gly435Arg, p.Leu479Val) disrupt homo-trimerization and DNA affinity, further supporting a loss-of-function mechanism (PMID:33798553). In vivo, CRISPR/Cas9-mediated myrf knockout and base editing in medaka fish recapitulate embryonic cardiac defects including hypoplastic ventricle, mirroring human CUGS phenotypes (PMID:37584388).

No studies have reported segregating familial variants, and all pathogenic alleles to date are de novo. There is no contradictory evidence challenging the MYRF–CUGS link. Integration of human genetics and functional models supports MYRF haploinsufficiency as the primary pathogenic mechanism in cardiac-urogenital syndrome.

Key Take-home: De novo loss-of-function variants in MYRF cause autosomal dominant cardiac-urogenital syndrome via haploinsufficiency, with robust functional validation in vitro and in vivo, enabling precise diagnosis and counseling.

References

• Frontiers in pediatrics • 2022 • 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. PMID:36467480
• PLoS genetics • 2018 • De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders. PMID:30532227
• Scientific reports • 2020 • Functional mechanism and pathogenic potential of MYRF ICA domain mutations implicated in birth defects. PMID:31964908
• The Journal of biological chemistry • 2021 • Functional mechanisms of MYRF DNA-binding domain mutations implicated in birth defects. PMID:33798553
• Disease models & mechanisms • 2023 • CRISPR-based knockout and base editing confirm the role of MYRF in heart development and congenital heart disease. PMID:37584388

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