Abstract 13076: A Rare Stopgain Variant in SLC25A2 Associates With Low Nitric Oxide and Poor Clinical Outcome in Hypoplastic Left Heart Syndrome

Abstract

Introduction: Mitochondrial respiration defects accompanied by low nitric oxide (NO) are associated with heart failure in congenital heart disease (CHD) patients with hypoplastic left heart syndrome (HLHS). Here we investigated the genetic etiology of low NO in patients with CHD. Hypothesis: Mutations in mitochondrial-related genes involved in NO metabolism contributes to the low NO associated risk for heart failure and need for heart transplantation in HLHS. Methods and Results: We performed a case-control association study among 588 white CHD cases including 41 with HLHS, and 24,143 white controls from the genome aggregation database (gnomAD). A rare conserved stopgain variant (rs562886845) in SLC25A2 encoding mitochondrial ornithine transporter was significantly enriched among the HLHS patients with poor clinical outcome (Group II, Table 1), with 15.8% carrying this mutation, yielding odds ratio of 17.07 ( p = 5.23 х 10 -4 ) in comparison to CHD patients without left ventricular outflow tract obstruction or 7.63 ( p =2.68 х 10 –3 ) in comparison to gnomAD control cohort. Significantly, SLC25A2 is the only mitochondrial transporter exporting asymmetric dimethylarginine, a natural NO synthase inhibitor. The three HLHS patients with this SLC25A2 variant showed very low nasal NO (nNO), a proxy for endogenous NO production capacity. All three patients had received heart transplant, with two being heterozygous and one homozygous for this variant. Significantly, the HLHS patient with the homozygous mutation had nNO at background levels (2.8 nl/min at 7 years of age as compared to >200 nl/min expected nNO). Conclusions: Our findings uncovered an essential role for SLC25A2 in determining NO production capacity in patients with HLHS. As all three HLHS patients with this variant and very low nNO survived with heart transplant, this variant should be further investigated as a genetic marker for predicting the need for early heart transplant in HLHS.