Diabetic medicine : a journal of the British Diabetic Association · 2025
Neonatal diabetes mellitus is a significant feature of COXPD-24 caused by recessive NARS2 variants.
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Donis Russell, Wakeling Matthew N, Jeffery Nicola, Govier Molly, Johnson Matthew B, Hassan Samar Sabir, Abdullah Mohammed Ahmed, Eltonbary Khadiga Yehia Elsayed, Parvaneh Nima, Amoli Mahsa M, Abbasi Farzaneh, Elmaoğulları Selin, Çetinkaya Semra, Gunes Kubra, Tayfun Meltem, Yaghootkar Hanieh, Hattersley Andrew T, Flanagan Sarah E, De Franco Elisa
Аннотация
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.
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.