Prevalence and phenotypic features of diabetes due to recessive, non-syndromic WFS1 mutations

in European Journal of Endocrinology
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  • 1 Department of Endocrinology, The Children’s Hospital Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, Zhejiang province, China
  • | 2 Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
  • | 3 Zhejiang MaiDa Gene Tech Co. Ltd, Zhoushan, Zhejiang Province, China

Correspondence should be addressed to J Fu or C Polychronakos; Email: fjf68@zju.edu.cn or constantin.polychronakos@mcgill.ca

*(M Zhu, Y Li and G Dong contributed equally to this work)

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Objective

Recessive WFS1 mutations are known to cause Wolfram syndrome, a very rare systemic disorder. However, they were also found in non-syndromic diabetes in Han Chinese misdiagnosed with type 1 diabetes (T1D), a molecular cause that appears to be considerably more common than the fully expressed syndrome. We aimed to better define the incidence and clinical features of non-syndromic diabetes due to recessive WFS1 mutation.

Design

We analyzed the genotype and phenotype of 320 consecutive incident Chinese pediatric diabetic patients diagnosed from 2016 to 2019 to search for non-syndromic diabetic cases due to recessive WFS1 mutation.

Methods

A cohort of 105 pancreatic autoantibody-negative patients were recruited for exome sequencing. All patients tested positive for pathogenic diallelic WFS1 mutations were examined for phenotypic features (fundoscopy, audiogram, and urine density).

Results

We found three cases of non-syndromic diabetes due to recessive WFS1 mutations (incidence = 0.94% (95% CI: 0.25–2.7%)). All three cases only had mild diabetes when diagnosed. All patients had well-conserved fasting C-peptide when diagnosed but one of them progressed to T1D-like insulin deficiency. In addition, we found a fourth case with previously undetected features of Wolfram syndrome.

Conclusions

Non-syndromic diabetes due to WFS1 mutation may be common among Chinese pediatric patients with diabetes. It is important to differentiate it from other maturity-onset diabetes in the young subtypes with similar phenotype by molecular diagnosis because of different prognosis and, potentially, therapy.

 

     European Society of Endocrinology

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