Cardiomyopathy due to PRDM16 mutation: First description of a fetal presentation, with possible modifier genes

Area of Science:

• Genetics
• Cardiology
• Developmental Biology

Background:

• Left ventricular non-compaction (LVNC) is a rare congenital cardiomyopathy.
• PRDM16, a gene encoding a transcription factor, is located in a chromosomal region associated with cardiomyopathy.
• Genetic factors underlying fetal cardiomyopathies are complex and often involve multiple genes.

Purpose of the Study:

• To report the first fetal case of LVNC associated with a PRDM16 gene variant.
• To investigate the genetic underpinnings of a severe fetal cardiac phenotype.
• To explore the potential role of PRDM16 and Titin (TTN) variants in fetal cardiomyopathy.

Main Methods:

• Fetal autopsy and histopathological examination.
• Exome sequencing (ES) for genetic analysis.
• Analysis of de novo and inherited genetic variants according to ACMG guidelines.

Main Results:

• A third-trimester fetus presented with hydrops fetalis, hydramnios, and hypokinetic heart, diagnosed with isolated cardiomegaly and left ventricular non-compaction with endocardial fibroelastosis post-termination.
• Exome sequencing identified a de novo, unreported nonsense variant (p.(Gln353*)) in the PRDM16 gene.
• Two rare variants of unknown significance (VOUS) in the Titin (TTN) gene were also identified, one de novo and one inherited.

Conclusions:

• A de novo PRDM16 variant is likely pathogenic and associated with fetal LVNC.
• Rare TTN variants may contribute to the severity and early onset of the cardiac phenotype in conjunction with the PRDM16 variant.
• Exome sequencing is a valuable tool for diagnosing genetic cardiomyopathies in fetal cases, where multiple genetic hits are common.