Background Idiopathic dilated cardiomyopathy (DCM) is recognised to be a heritable disorder, yet clinical genetic testing does not produce a diagnosis in >50% of paediatric patients. Identifying a genetic cause is crucial because this knowledge can affect management options, cardiac surveillance in relatives and reproductive decision-making. In this study, we sought to identify the underlying genetic defect in a patient born to consanguineous parents with rapidly progressive DCM that led to death in early infancy.
Methods and results Exome sequencing revealed a potentially pathogenic, homozygous missense variant, c.542G>T, p.(Gly181Val), in SOD2. This gene encodes superoxide dismutase 2 (SOD2) or manganese-superoxide dismutase, a mitochondrial matrix protein that scavenges oxygen radicals produced by oxidation-reduction and electron transport reactions occurring in mitochondria via conversion of superoxide anion (O2–·) into H2O2. Measurement of hydroethidine oxidation showed a significant increase in O2−· levels in the patient’s skin fibroblasts, as compared with controls, and this was paralleled by reduced catalytic activity of SOD2 in patient fibroblasts and muscle. Lentiviral complementation experiments demonstrated that mitochondrial SOD2 activity could be completely restored on transduction with wild type SOD2.
Conclusion Our results provide evidence that defective SOD2 may lead to toxic increases in the levels of damaging oxygen radicals in the neonatal heart, which can result in rapidly developing heart failure and death. We propose SOD2 as a novel nuclear-encoded mitochondrial protein involved in severe human neonatal cardiomyopathy, thus expanding the wide range of genetic factors involved in paediatric cardiomyopathies.
- clinical genetics
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RA and JCH are joint first authors.
Contributors JCH acquired the clinical data, analysed and interpreted data, codrafted the initial manuscript and revised and submitted the manuscript. RA and AP performed laboratory work, analysed and interpreted data and codrafted the initial manuscript. JGP, JMAV and MWW acquired the clinical data and critically reviewed the manuscript. LGB performed laboratory work and analysed and interpreted data. PAZ interpreted the data. PHGMW, IHV, LTW, RJR, PGJN and KEN performed laboratory work, interpreted data and critically reviewed the manuscript. RJS developed laboratory and analytical logistics and critically reviewed the manuscript. JPT and MPB critically reviewed the manuscript. JDHJ initiated, conceptualised and designed the study, interpreted data and critically reviewed the manuscript. All authors approved the final manuscript as submitted.
Funding RA was supported by the Netherlands Heart Foundation (grant 2010B164).
Competing interests PHGMW is scientific advisor of Khondrion, Nijmegen, the Netherlands. This SME had no involvement in the data collection, analysis and interpretation, writing of the manuscript and in the decision to submit the manuscript for publication.
Patient consent for publication Next of kin consent obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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