High prevalence of a monogenic cause in Han Chinese diagnosed with type 1 diabetes, partly driven by non-syndromic recessive WFS1 mutations.

It is estimated that ∼1% of European-ancestry patients clinically diagnosed with type 1 diabetes (T1D) actually have monogenic forms of the disease. Because of the much lower incidence of true T1D in East Asians, we hypothesised that the percentage would be much higher. To test this, we sequenced the exome of 82 Chinese Han patients clinically diagnosed as T1D but negative for three autoantibodies. Analysis focused on established or proposed mongenic diabetes genes. We found credible mutations in 18 of the 82 autoantibody-negative patients (19.5%). All mutations had consensus pathogenicity support by five algorithms. As in Europeans, the most common gene was HNF1A (MODY3), in 6/18 cases. Surprisingly, almost as frequent were diallelic mutations in WFS1, known to cause Wolfram syndrome but also described in non-syndromic cases. Fasting C-peptide varied widely and was not predictive. Given the 27.4% autoantibody negativity in Chinese and 22% mutation rate, we estimate that around 6% of Chinese with a clinical T1D diagnosis have monogenic diabetes. Our findings support universal sequencing of autoantibody-negative cases as standard of care in East Asian patients with a clinical T1D diagnosis. Non-syndromic diabetes with WSF1 mutations is not rare in Chinese. Its response to alternative treatments should be investigated.