Abstract
BACKGROUND: Recessive loss-of-function NARS2 variants causing the multi-system disorder Combined oxidative phosphorylation deficiency 24 (COXPD24) have recently been reported in 3 individuals with diabetes diagnosed between 3 days and 14 months of age. In this study, we investigate the presence of NARS2 variants in a large cohort of individuals with early-onset diabetes. METHODS: We used genome and targeted next-generation sequencing to screen for rare, coding biallelic NARS2 variants in a cohort of 397 individuals diagnosed with diabetes <24 months of age of unknown genetic cause. RESULTS: We identified 8 individuals with homozygous disease-causing missense variants in NARS2 (4 individuals with the p.(Phe216Leu) variant, 3 with p.(Thr180Asn) and one with p.(Val440Leu)). All 8 individuals were diagnosed with insulin-dependent diabetes before 6 months of age (neonatal diabetes, NDM) with the median age at diagnosis being 4 weeks (range: 1 to 20 weeks). 7/8 probands had low birthweight (median Z-score: -2.43, range: -4.17 to 0.86). Neurological features were common, with epilepsy and developmental delay each identified in 7/8 and 6/8 participants, respectively. CONCLUSION: Taken together with previously published cases, this study shows that NDM is an important feature of COXPD-24 and highlights a critical role for NARS2 in the insulin-secreting pancreatic β-cell.