<i>MGRN1</i> is linked to recessive heart and laterality defects: the first genotype-phenotype report in humans

Recurrent idiopathic severe fetal structural anomalies present major challenges for reproductive decision-making and genetic counselling. A non-consanguineous healthy Estonian couple had experienced two electively terminated pregnancies at 12-13 weeks' gestation due to unexplained major fetal malformations and one early miscarriage. Their three pregnancies had resulted in unaffected newborns. Exome sequencing of fetal tissues from both terminated pregnancies identified a homozygous rare missense variant in <i>MGRN1</i> (mahogunin ring finger 1), c.881G>A, p.(Arg294His) (Genome Aggregation Database V.4.1.0 allele frequency<8×10⁻⁵; no homozygotes reported in any population database). MGRN1 functions as an E3 ubiquitin ligase critical for protein homeostasis and developmental signalling. The detected substitution compromises a conserved residue within the RING (Really Interesting New Gene) finger domain. Cascade testing revealed that the parents and one unaffected child were heterozygous carriers, while two healthy siblings were homozygous for the reference allele. Both affected fetuses displayed congenital malformations closely mirroring prenatal phenotypes reported in <i>Mgrn1</i> homozygous mutant mice, including cardiac malformations (ventricular septal defect, outflow tract malposition, pulmonary artery hypoplasia) and abnormal left-right axis patterning. These findings provide the first evidence implicating <i>MGRN1</i> in human congenital disease and support its role in early embryonic patterning.