Abstract
BACKGROUND: Mulibrey nanism is a rare autosomal recessive genetic disorder caused by homozygous or compound heterozygous mutations in the tripartite motif protein 37 (TRIM37 gene), which codes for a RING finger E3 ubiquitin ligase. Affected individuals present with prenatal-onset growth failure, abnormalities in multiple organs, and heart disorders, including constrictive pericarditis and restrictive cardiomyopathy. METHODS AND RESULTS: We performed phenotypic-genotypic analyses in a 32-week gestation preterm infant presenting with a complex congenital heart disease, including interrupted aortic arch type B, persistent left-sided superior vena cava (SVC), septal defects, and valvular disease, in addition to other congenital malformations. Initial genetic screenings, including whole genome chromosomal microarray, were negative. Whole exome sequencing (WES) of DNA samples from the proband/mother duo revealed two novel heterozygous missense variants [c.199C>T (p.Arg67Cys)] and [c.2041C>G (p.Gln681Glu)] in the TRIM37 gene, which has been associated with Mulibrey nanism. The c.199C>T variant was inherited from the mother; however, the mode of inheritance of the c.2041C>G could not be ascertained. Whether the two variants are present on the same allele could not be determined either, due to the unavailability of the father or any family member for additional genetic analysis. However, in silico analysis predicted that both variants are damaging, and both amino acid positions are fairly well conserved. CONCLUSION: These findings highlight the critical role of the TRIM37 genetic variants in complex congenital heart defect phenotypes associated with Mulibrey nanism and emphasize the importance of comprehensive triobased WES for antenatal care and early diagnosis.