Segregation of two variants suggests the presence of autosomal dominant and recessive forms of WFS1-related disease within the same family: expanding the phenotypic spectrum of Wolfram Syndrome

2019 ◽  
Vol 57 (2) ◽  
pp. 121-123 ◽  
Author(s):  
Laina Lusk ◽  
Emily Black ◽  
Jaime Vengoechea
Keyword(s):  
Hearing Loss ◽  
Optic Atrophy ◽  
Autosomal Dominant ◽  
Phenotypic Variability ◽  
Wolfram Syndrome ◽  
Related Disease ◽  
Uncertain Significance ◽  
Similar Phenotype ◽  
Biallelic Mutations ◽  
Clinical Counselling

BackgroundWFS1 was initially described as causative agent of autosomal recessive (AR) Wolfram syndrome, a childhood-onset disorder involving diabetes, optic atrophy, hearing loss and neurodegenerative features. However, the discovery of autosomal dominant (AD) disorders caused by this gene has resulted in clinical counselling and result interpretation challenges.ObjectiveWe seek to report a family that appears to segregate dominant and recessive forms of WFS1-related disease.Methods/resultsA 19-year-old woman presented with progressive childhood sensorineural hearing loss and recent optic atrophy, with biallelic mutations in WFS1: c.2486T>C (likely pathogenic) and c.2470G>A (uncertain significance). Her A1C was normal. Her sister carried the same variants and had a similar phenotype. Their father carried c.2486T>C and was found to have mild–moderate hearing loss but no optic atrophy or neurological symptoms. The mother carried c.2470G>A and had a normal audiogram and ophthalmological exam. Providing anticipatory guidance for this family was difficult given the phenotypic variability of WFS1-related disorders and the uncertainty surrounding whether the inheritance pattern was AR or AD.ConclusionThe clinical correlation of the variants identified in this family suggests an AR Wolfram-like syndrome, without the typical diabetes mellitus or diabetes insipidus nor neurological decline. To our knowledge, this is a novel WFS1-related phenotype.

scholarly journals Wolfram Syndrome: A Case Report and Review of Clinical Manifestations, Genetics Pathophysiology, and Potential Therapies

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
N. B. Toppings ◽  
J. M. McMillan ◽  
P. Y. B. Au ◽  
O. Suchowersky ◽  
L. E. Donovan
Keyword(s):  
Diabetes Mellitus ◽  
Optic Atrophy ◽  
Cell Function ◽  
Clinical Manifestations ◽  
Autosomal Recessive Disorder ◽  
Wolfram Syndrome ◽  
Biallelic Mutations ◽  
Therapeutic Considerations

Background.Classical Wolfram syndrome (WS) is a rare autosomal recessive disorder caused by mutations inWFS1,a gene implicated in endoplasmic reticulum (ER) and mitochondrial function. WS is characterized by insulin-requiring diabetes mellitus and optic atrophy. A constellation of other features contributes to the acronym DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). This review seeks to raise awareness of this rare form of diabetes so that individuals with WS are identified and provided with appropriate care.Case.We describe a woman without risk factors for gestational or type 2 diabetes who presented with gestational diabetes (GDM) at the age of 39 years during her first and only pregnancy. Although she had optic atrophy since the age of 10 years, WS was not considered as her diagnosis until she presented with GDM. Biallelic mutations inWFS1were identified, supporting a diagnosis of classical WS.Conclusions.The distinct natural history, complications, and differences in management reinforce the importance of distinguishing WS from other forms of diabetes. Recent advances in the genetics and pathophysiology of WS have led to promising new therapeutic considerations that may preserveβ-cell function and slow progressive neurological decline. Insight into the pathophysiology of WS may also inform strategies forβ-cell preservation for individuals with type 1 and 2 diabetes.

A mutation in Wolfram syndrome type 1 gene in a Japanese family with autosomal dominant low-frequency sensorineural hearing loss

2005 ◽  
Vol 125 (11) ◽  
pp. 1189-1194 ◽  
Author(s):  
Yoshihiro Noguchi ◽  
Takatoshi Yashima ◽  
Akio Hatanaka ◽  
Masamichi Uzawa ◽  
Michio Yasunami ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Autosomal Dominant ◽  
Low Frequency ◽  
Wolfram Syndrome ◽  
Sensorineural Hearing ◽  
Syndrome Type ◽  
Japanese Family

scholarly journals A splice-site mutation and overexpression of MYO6 cause a similar phenotype in two families with autosomal dominant hearing loss

2008 ◽  
Vol 16 (5) ◽  
pp. 593-602 ◽  
Author(s):  
Nele Hilgert ◽  
Vedat Topsakal ◽  
Joost van Dinther ◽  
Erwin Offeciers ◽  
Paul Van de Heyning ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Splice Site ◽  
Autosomal Dominant ◽  
Splice Site Mutation ◽  
Site Mutation ◽  
Similar Phenotype

scholarly journals Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Tian-Yi Cui ◽  
Xue Gao ◽  
Sha-Sha Huang ◽  
Yan-Yan Sun ◽  
Si-Qi Zhang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Dominant ◽  
Asian Population ◽  
Nonsyndromic Hearing Loss ◽  
Hereditary Hearing Loss ◽  
Variant Of Uncertain Significance ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Uncertain Significance

Hereditary hearing loss is one of the most common sensory disabilities worldwide. Mutation of POU domain class 4 transcription factor 3 (POU4F3) is considered the pathogenic cause of autosomal dominant nonsyndromic hearing loss (ADNSHL), designated as autosomal dominant nonsyndromic deafness 15. In this study, four novel variants in POU4F3, c.696G>T (p.Glu232Asp), c.325C>T (p.His109Tyr), c.635T>C (p.Leu212Pro), and c.183delG (p.Ala62Argfs∗22), were identified in four different Chinese families with ADNSHL by targeted next-generation sequencing and Sanger sequencing. Based on the American College of Medical Genetics and Genomics guidelines, c.183delG (p.Ala62Argfs∗22) is classified as a pathogenic variant, c.696G>T (p.Glu232Asp) and c.635T>C (p.Leu212Pro) are classified as likely pathogenic variants, and c.325C>T (p.His109Tyr) is classified as a variant of uncertain significance. Based on previous reports and the results of this study, we speculated that POU4F3 pathogenic variants are significant contributors to ADNSHL in the East Asian population. Therefore, screening of POU4F3 should be a routine examination for the diagnosis of hereditary hearing loss.

Progressive autosomal dominant optic atrophy and sensorineural hearing loss in a Turkish family

2002 ◽  
Vol 23 (1) ◽  
pp. 29-36 ◽  
Author(s):  
Serap Özden ◽  
Füsun Düzcan ◽  
Bernd Wollnik ◽  
G. Ozan Çetin ◽  
Türker Sahiner ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Optic Atrophy ◽  
Autosomal Dominant ◽  
Sensorineural Hearing ◽  
Autosomal Dominant Optic Atrophy ◽  
Dominant Optic Atrophy ◽  
Turkish Family

scholarly journals WFS1 protein expression correlates with clinical progression of optic atrophy in patients with Wolfram syndrome

2021 ◽  
pp. jmedgenet-2020-107257
Author(s):  
Kun Hu ◽  
Malgorzata Zatyka ◽  
Dewi Astuti ◽  
Nicola Beer ◽  
Renuka P Dias ◽  
...  
Keyword(s):  
Protein Expression ◽  
Er Stress ◽  
Optic Atrophy ◽  
Wolfram Syndrome ◽  
Luciferase Reporter ◽  
Compound Heterozygous ◽  
Nonsense Mutations ◽  
Functional Studies ◽  
Unfolded Protein ◽  
Protein Response

BackgroundWolfram syndrome (WFS) is a rare disorder characterised by childhood-onset diabetes mellitus and progressive optic atrophy. Most patients have variants in the WFS1 gene. We undertook functional studies of WFS1 variants and correlated these with WFS1 protein expression and phenotype.Methods9 patients with a clinical diagnosis of WFS were studied with quantitative PCR for markers of endoplasmic reticulum (ER) stress and immunoblotting of fibroblast protein extracts for WFS1 protein expression. Luciferase reporter assay was used to assess ATF-6 dependent unfolded protein response (UPR) activation.Results6 patients with compound heterozygous nonsense mutations in WFS1 had no detectable WFS1 protein expression; 3 patients with missense variants had 4%, 45% and 48% WFS1 protein expression. One of these also had an OPA1 mutation and was reclassified as autosomal dominant optic atrophy-plus syndrome. There were no correlations between ER stress marker mRNA and WFS1 protein expression. ERSE-luciferase reporter indicated activation of the ATF6 branch of UPR in two patients tested. Patients with partial WFS1 expression showed milder visual acuity impairment (asymptomatic or colour blind only), compared with those with absent expression (registered severe vision impaired) (p=0.04). These differences remained after adjusting for duration of optic atrophy.ConclusionsPatients with WFS who have partial WFS1 protein expression present with milder visual impairment. This suggests a protective effect of partial WFS1 protein expression on the severity and perhaps progression of vision impairment and that therapies to increase residual WFS1 protein expression may be beneficial.

scholarly journals Expanding the genetic spectrum of primary familial brain calcification due to SLC2OA2 mutations: a case series

Neurogenetics ◽  
2021 ◽  
Author(s):  
Luca Magistrelli ◽  
Roberta Croce ◽  
Fabiola De Marchi ◽  
Chiara Basagni ◽  
Miryam Carecchio ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Case Series ◽  
Dominant Trait ◽  
Autosomal Dominant Trait ◽  
Phenotypic Spectrum ◽  
Primary Familial Brain Calcification ◽  
Psychiatric Disturbances ◽  
Brain Calcification ◽  
Uncertain Significance ◽  
Six Genes

AbstractPrimary familial brain calcification (PFBC) is a neurological condition characterized by the presence of intracranial calcifications, mainly involving basal ganglia, thalamus, and dentate nuclei. So far, six genes have been linked to this condition: SLC20A2, PDGFRB, PDGFB, and XPR1 inherited as autosomal-dominant trait, while MYORG and JAM2 present a recessive pattern of inheritance. Patients mainly present with movement disorders, psychiatric disturbances, and cognitive decline or are completely asymptomatic and calcifications may represent an occasional finding. Here we present three variants in SLC20A2, two exonic and one intronic, which we found in patients with PFBC associated to three different clinical phenotypes. One variant is novel and two were already described as variants of uncertain significance. We confirm the pathogenicity of these three variants and suggest a broadening of the phenotypic spectrum associated with mutations in SLC20A2.

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