期刊
DIABETES
卷 66, 期 7, 页码 2044-2053出版社
AMER DIABETES ASSOC
DOI: 10.2337/db16-1296
关键词
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资金
- Wellcome Trust [WT098395/Z/12/Z, 105636/Z/14/Z]
- National Institute for Health Research
- Royal Society [105636/Z/14/Z]
- National Institutes of Health [DK020579, UL1 TR000448]
- National Institute for Health Research [NF-SI-0611-10219, NF-SI-0616-10080] Funding Source: researchfish
- Wellcome Trust [098395/Z/12/Z] Funding Source: researchfish
Neonatal diabetes is frequently part of a complex syndrome with extrapancreatic features: 18 genes causing syndromic neonatal diabetes have been identified to date. There are still patients with neonatal diabetes who have novel genetic syndromes. We performed exome sequencing in a patient and his unrelated, unaffected parents to identify the genetic etiology of a syndrome characterized by neonatal diabetes, sensorineural deafness, and congenital cataracts. Further testing was performed in 311 patients with diabetes diagnosed before 1 year of age in whom all known genetic causes had been excluded. We identified 5 patients, including the initial case, with three heterozygous missense mutations in WFS1 (4/5 confirmed de novo). They had diabetes diagnosed before 12 months (2 before 6 months) (5/5), sensorineural deafness diagnosed soon after birth (5/5), congenital cataracts (4/5), and hypotonia (4/5). In vitro studies showed that these WFS1 mutations are functionally different from the known recessive Wolfram syndrome-causing mutations, as they tend to aggregate and induce robust endoplasmic reticulum stress. Our results establish specific dominant WFS1 mutations as a cause of a novel syndrome including neonatal/infancy-onset diabetes, congenital cataracts, and sensorineural deafness. This syndrome has a discrete pathophysiology and differs genetically and clinically from recessive Wolfram syndrome.
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