# Prevalence and Clinical Characteristics of NEUROD1‐MODY in Chinese Early‐Onset Type 2 Diabetes Mellitus and a Literature Review

## TL;DR

This study finds that NEUROD1-MODY is rare in Chinese patients with early-onset type 2 diabetes and identifies a variant that may cause the condition more commonly in Chinese individuals.

## Contribution

The first prevalence estimation of NEUROD1-MODY in Chinese early-onset type 2 diabetes patients and identification of a potentially significant variant.

## Key findings

- NEUROD1-MODY prevalence in Chinese early-onset type 2 diabetes is less than 0.15%.
- The P197H variant reduces insulin promoter transcriptional activity by nearly 50%.
- Asian patients with NEUROD1-MODY show distinct clinical features compared to Caucasians.

## Abstract

Maturity‐onset diabetes of the young resulting from mutations of the NEUROD1 gene (NEUROD1‐MODY) is a rare form of diabetes and has not been well studied. We aimed to estimate its prevalence in Chinese patients with early‐onset type 2 diabetes mellitus (EOD) and summarize its clinical and genetic characteristics.

We performed next‐generation sequencing in 679 patients with EOD to screen rare variants in NEUROD1 exons and evaluated the effects of variants using in vitro experiments. All the reported NEUROD1‐MODY cases were reviewed. Patients carrying pathogenic or likely pathogenic variants were diagnosed with NEUROD1‐MODY according to the American College of Medical Genetics and Genomics guidelines.

Four rare variants were identified in 679 patients with EOD, but only P197H decreased the transcriptional activity in in vitro functional assays to an extent comparable to the well‐known mutation causing NEUROD1‐MODY. Its frequency was pretty higher in the European population (0.024) than that in the East Asian population (0.00034) according to the gnomAD database. Twenty‐eight previously reported patients could be confirmed as diagnosed. The patients in Asia had a lower body mass index and a higher rate of ketosis compared with Caucasians, and the mutations present in Asia often occurred in the transactivation domain. Neurological abnormalities were observed in 10.7% of the patients with NEUROD1‐MODY.

NEUROD1‐MODY in Chinese patients with EOD is not common (≤ 0.15%). The P197H might account for MODY in Chinese with a higher penetrance than Caucasian and needs further exploration. The possible differences of phenotypes exist between the two ethnic populations.

We, for the first time, calculated that the prevalence of NEUROD1‐MODY was less than 0.15% in Chinese patients with early‐onset type 2 diabetes mellitus. The p.P197H variant of the NEUROD1 gene significantly decreased the transcriptional activity of the insulin promoter by nearly 50% compared with that of the wild type. This variant might result in MODY in Chinese individuals with a higher penetrance than Caucasians. The possible differences of NEUROD1‐MODY phenotypes exist between Asians and Caucasians.