SECISBP2 Deficiency Causes a Lethal Perinatal Cardiomyopathy

Selenoproteins are a specialised group of proteins that incorporate selenium, an essential micronutrient, in the form of selenocysteine. The SECIS binding protein 2 (SBP2), encoded by SECISBP2, is a crucial component of the selenocysteine incorporation machinery. SECISBP2 deficiency compromises selenoprotein synthesis, and its knockout causes embryonic lethality in mice. Selenium is critical to cardiac function, and nutritional deficiency causes Keshan disease, a progressive cardiomyopathy. Biallelic variants in SECISBP2 cause pleiotropic phenotypes including abnormal thyroid hormone metabolism, neurodevelopmental disorders and aortic aneurysms. No reported phenotypes to date include cardiomyopathy. We report a consanguineous South Asian family with a history of perinatal deaths due to progressive cardiomyopathy and intractable arrhythmias with a rare homozygous loss-of-function splice site variant in SECISBP2. The SECISBP2 c.1303-2A>G variant was homozygous in four affected offspring and heterozygous in the parents. One child without cardiac disease did not carry this variant. RNA sequencing confirmed that almost all transcripts would undergo nonsense-mediated decay. Further, we observed a pronounced decrease in GPX1 and SELENOH selenoprotein mRNA, as well as a large decrease in SELENOH, GPX1, GPX3 and GPX4 cardiac protein abundance in homozygotes, a molecular hallmark of SECISBP2 deficiency. Notably, we observed a >12-fold decrease in cardiac GPX4, a key selenoprotein that suppresses lipid peroxidation and ferroptosis, suggesting a possible ferroptosis-mediated mechanism for heart failure. Our analysis suggests that c.1303-2A>G is likely the most damaging homozygous variant discovered to date. For the first time, we show that SECISBP2 is essential for human life, with almost complete loss-of-function causing a lethal perinatal cardiomyopathy characterised by pronounced cardiac selenoprotein loss.