SECISBP2 Deficiency Causes a Lethal Perinatal Cardiomyopathy

Homozygous loss-of-function splice site variant in SECISBP2 (c.1303-2A>G); RNA sequencing confirms that almost all transcripts undergo nonsense-mediated decay, with collapse of cardiac selenoproteins (SELENOH, GPX1, GPX3, GPX4) and a more than 12-fold decrease in GPX4, suggesting a ferroptosis-mediated mechanism of heart failure.

Biallelic variants in SECISBP2, an essential component of the selenocysteine incorporation machinery, are known to cause pleiotropic phenotypes — abnormal thyroid hormone metabolism, neurodevelopmental disorders, aortic aneurysms — but no cardiomyopathy had been reported to date. The authors describe a consanguineous South Asian family with perinatal deaths from progressive cardiomyopathy and intractable arrhythmias, carrying a rare loss-of-function splice site variant (SECISBP2 c.1303-2A>G) homozygous in four affected offspring and heterozygous in the parents; one unaffected child did not carry the variant. RNA sequencing confirmed that almost all transcripts undergo nonsense-mediated decay, with a marked fall in cardiac selenoprotein mRNA and protein, including a more than 12-fold decrease in GPX4. The authors conclude that SECISBP2 is essential for human life, with near-complete loss of function causing a lethal perinatal cardiomyopathy.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A clear, well-argued phenotypic expansion: four affected children, a segregating variant and direct molecular evidence at RNA and cardiac protein level. For a laboratory, this justifies looking at SECISBP2 in unexplained severe perinatal cardiomyopathy, particularly with consanguinity, even without the usual thyroid signs. The ferroptosis hypothesis is inferred from the protein profile, and this is a single family in a preprint — to be confirmed before broad use in genetic counselling.

Analysis by Dr Thibaut Benquey