Identification of a missense variant in the WFS1 gene that causes a mild form of Wolfram syndrome and is associated with risk for type 2 diabetes in Ashkenazi Jewish individuals

Bansal, Vikas; Boehm, Bernhard O.; Darvasi, Ariel

doi:10.1007/s00125-018-4690-3

Cited by 44 publications

(48 citation statements)

References 41 publications

(71 reference statements)

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“…Our other important finding is the high prevalence of nonsyndromic WFS1 cases, much more common than WS and comparable with that reported in consanguineous families in Lebanon (11), in a nonconsangineous population. Nonsyndromic diabetes has also been reported with homozygosity for a nonsynonymous variant frequently found in Ashkenazi Jewish individuals (20), but it is clearly not confined to that variant. The therapeutic implications of this diagnostic reassignment remain to be seen, but successful use of incretin interventions has been reported (21,22).…”

Section: Discussionmentioning

confidence: 99%

High Prevalence of a Monogenic Cause in Han Chinese Diagnosed With Type 1 Diabetes, Partly Driven by Nonsyndromic Recessive WFS1 Mutations

Wang

et al. 2019

Diabetes

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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 hypothesized that the percentage would be much higher. To test this, we sequenced the exome of 82 Chinese Han patients clinically diagnosed with T1D but negative for three autoantibodies. Analysis focused on established or proposed monogenic diabetes genes. We found credible mutations in 18 of the 82 autoantibody-negative patients (22%). All mutations had consensus pathogenicity support by five algorithms. As in Europeans, the most common gene was HNF1A (MODY3), in 6 of 18 cases. Surprisingly, almost as frequent were diallelic mutations in WFS1, known to cause Wolfram syndrome but also described in nonsyndromic 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 ∼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. Nonsyndromic diabetes with WSF1 mutations is not rare in Chinese. Its response to alternative treatments should be investigated.

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Section: Discussionmentioning

confidence: 99%

High Prevalence of a Monogenic Cause in Han Chinese Diagnosed With Type 1 Diabetes, Partly Driven by Nonsyndromic Recessive WFS1 Mutations

Wang

et al. 2019

Diabetes

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“…Mutations in WFS1 gene are responsible for most WFS patients. Since the discovery of WFS1 in 1998, more than 300 different mutations have been identified in this gene [34] and majority of them located in the exon 8 encoding the nine transmembrane segments and the C-terminal tail of wolframin [33]. In this study, we found four missense mutations located in exon 8 of WFS1 , two of them were first reported including c.1618 T > G (p.Trp540Gly) and c.1048 T > A (p.Phe350Ile).…”

Section: Discussionmentioning

confidence: 99%

Novel mutations and the ophthalmologic characters in Chinese patients with Wolfram Syndrome

Zhang

Kong

et al. 2019

Orphanet J Rare Dis

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Background Wolfram Syndrome (WFS) is a rare autosomal recessive neurodegenerative disease which has a wide spectrum of manifestations including diabetes insipidus, diabetes mellitus, optic atrophy and deafness. WFS1 and CISD2 are two main causing genes of WFS. The aim of this study was to illustrate the ophthalmologic manifestations and determine the genotype of Chinese WFS patients. Results Completed ophthalmic examinations and family investigations were performed on 4 clinically diagnosed WFS patients from 4 unrelated families. Genetic testing was done by the next generation sequencing of candidate genes. One patient carried a homozygous mutation (c.272_273del) in CISD2 , two patients carried compound heterozygous mutations (c.1618 T > G + c.2020G > A and c.1048 T > A + c.2020G > A) in WFS1 , and one patient carried a heterozygous mutation (c.937C > T) in WFS1 . Three of them were novel mutations. Conclusions Our study indicated WFS in Chinese is a neurodegenerative disease with both wide spectrum of clinical features and genetic heterogeneity. We found three novel mutations in WFS patients, and to our best knowledge, this is the first report of Chinese WFS patient with mutation in CISD2 . Electronic supplementary material The online version of this article (10.1186/s13023-019-1161-y) contains supplementary material, which is available to authorized users.

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“…Patient # 8 presented with asymptomatic optic atrophy (correctable vision loss) and was identified to have a pathogenic variant ( WFS1 c.1941C>A; p.Cys647) [38,39] and a VUS (c.1597C>T; p.Pro533Ser) in trans (Table 1) [40]. Patient # 97 had bilateral vision loss and was homozygous for a missense variant (c.1672C>T; p.Arg558Cys) [41,42]. At 33 and 39 years of age, respectively, neither individual had diabetes nor hearing loss, two of the canonical features of Wolfram syndrome.…”

Section: Discussionmentioning

confidence: 99%

An evaluation of genetic causes and environmental risks for bilateral optic atrophy

et al. 2019

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PurposeTo assess the clinical utility of next-generation sequencing (NGS) for the diagnosis of patients with optic atrophy (OA).DesignRetrospective cohort study.Methods97 patients were referred to the McMaster University Medical Center (Hamilton, Ontario) for evaluation of bilateral OA. All patients were sent for NGS including a 22 nuclear gene panel and/or complete mitochondrial DNA (mtDNA) sequencing. Positive genetic test results and abnormal vibration sensation were compared in patients +/- environmental exposures or a family history.Results19/94 (20.2%) had a positive nuclear variant, of which 15/19 (78.9%) were in the OPA1 gene. No positive mtDNA variants were identified. The detection of a positive genetic variant was significantly different in patients who reported excessive ethanol use, but not in patients who smoke (0/19 (0%) vs. 19/78 (24.4%), P = 0.0164 and 4/22 (18.2%) vs. 15/74 (20.3%), P = 0.829, respectively). Patients with a positive family history were more likely to have a positive genetic variant compared to patients with a negative family history (P = 0.0112). There were significantly more excessive drinkers with an abnormal vibration sensation (P = 0.026), and with a similar trend in smokers (P = 0.074).ConclusionsAll positive genetic variants were identified in nuclear genes. We identified a potential independent pathophysiological link between a history of excessive ethanol consumption and bilateral OA. Further investigations should evaluate and identify potential environmental risk factors for OA.

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Identification of a missense variant in the WFS1 gene that causes a mild form of Wolfram syndrome and is associated with risk for type 2 diabetes in Ashkenazi Jewish individuals

Cited by 44 publications

References 41 publications

High Prevalence of a Monogenic Cause in Han Chinese Diagnosed With Type 1 Diabetes, Partly Driven by Nonsyndromic Recessive WFS1 Mutations

High Prevalence of a Monogenic Cause in Han Chinese Diagnosed With Type 1 Diabetes, Partly Driven by Nonsyndromic Recessive WFS1 Mutations

Novel mutations and the ophthalmologic characters in Chinese patients with Wolfram Syndrome

An evaluation of genetic causes and environmental risks for bilateral optic atrophy

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