NEUROD1 – NeuroD1‐related Maturity-Onset Diabetes of the Young (MODY6)

Heterozygous NEUROD1 variants have been identified as a rare cause of MODY6, with three affected individuals in two unrelated families demonstrating autosomal dominant inheritance. A novel missense variant, c.340A>C (p.Met114Leu), was discovered by whole-exome sequencing in a French pedigree and co-segregated with early-onset, non–insulin-dependent diabetes in the proband, sister and mother, with variable age of onset ([PMID:32184107]). A second family reported a de novo NEUROD1 missense variant in a young Chinese patient presenting with MODY features alongside Charcot-Marie-Tooth disease type 1A ([PMID:40026692]). Functional studies in beta-cell lines and animal models support a haploinsufficiency mechanism: NEUROD1 inactivation impairs insulin gene transcription, reduces beta-cell differentiation, and recapitulates hyperglycaemia ([PMID:17440689]). However, large screening series in MODY and type 2 diabetes cohorts failed to identify recurrent NEUROD1 mutations, indicating low prevalence and incomplete penetrance in broader populations ([PMID:10230653]).

Key clinical features include polyuria and polydipsia with persistent fasting hyperglycaemia; recognition of NEUROD1-MODY influences therapy choice and family screening. Given limited human data but consistent functional concordance, NEUROD1 is classified with limited clinical validity for MODY6. Early genetic diagnosis enables precision management of affected individuals.

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