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

Lusk, Laina; Black, Emily; Vengoechea, Jaime

doi:10.1136/jmedgenet-2018-105782

Cited by 9 publications

(4 citation statements)

References 12 publications

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“…Like classic recessive forms of WS, patients with AD disease also manifest clinical heterogeneity; however, manifestations can be less severe. Some dominant variants in WFS1 are associated with diabetes mellitus, optic nerve atrophy, cataracts, deafness, and psychiatric illness [3, 4, 15, 16, 19]. Similar to previous reports, none of the family members in our case had any other features of classic recessive WS.…”

Section: Discussion/conclusionsupporting

confidence: 88%

“…Whereas the vast majority of WS patients have the classic recessive form, there are numerous reports of pathogenic autosomal dominant (AD) variants in the WFS1 gene leading to distinct forms of the disorder, termed WFS1-related disorders [3, 4, 15-18]. Recently, there has been great interest in repurposing drugs that restore normal ER function, calcium homeostasis, and/or alleviate ER stress [2, 3, 8].…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of GLP-1 Agonist Therapy in Autosomal Dominant WFS1-Related Disorder: A Case Report

Scully

Wolfsdorf²

2020

Horm Res Paediatr

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Background: Wolfram syndrome is a rare neurodegenerative disorder, characterized by the presence of diabetes insipidus, diabetes mellitus, optic atrophy, and sensorineural deafness. The majority of cases are due to autosomal recessive biallelic variants in the WFS1 gene; however, pathogenic autosomal dominant (AD) mutations have also been described. Glucagon-like peptide (GLP-1) agonists have been studied in both animal models and humans with classic Wolfram syndrome. Case: We present a 15-year-old female with a personal and family history of congenital strabismus, bilateral cataracts, low-frequency sensorineural hearing loss, and diabetes mellitus. Trio whole exome sequencing revealed a previously unknown maternally inherited heterozygous variant in exon 8 of the WFS1 gene c.2605_2616del12 p.Ser869_His872del, leading to the diagnosis of AD WFS1-related disorder. Treatment with a GLP-1 agonist resulted in marked improvement in glycemic control and discontinuation of insulin therapy. This patient’s response to a GLP-1 agonist provides suggestive indirect evidence for a role of WFS1 on β-cell endoplasmic reticulum stress and suggests that treatment with a GLP-1 agonist should be considered in patients with dominant forms of WS.

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Section: Discussion/conclusionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Efficacy of GLP-1 Agonist Therapy in Autosomal Dominant WFS1-Related Disorder: A Case Report

Scully

Wolfsdorf²

2020

Horm Res Paediatr

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“…The clinical phenotype was complex and lacked the correlation of gene variation on protein function. In the same family, WFS1 variants can also lead to different clinical phenotypes, and the presence of autosomal dominant and recessive WFS1 -related disorders has been described in the same family ( 24 ). The lack of genotype-phenotype correlations for WFS1 variants was also further supported by observations in the probands and their family members in our study.…”

Section: Discussionmentioning

confidence: 99%

Complex clinical manifestations and new insights in RNA sequencing of children with diabetes and WFS1 variants

Ding

Li²,

Zhang³

et al. 2023

Front. Endocrinol.

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BackgroundWFS1-related disorders involve a wide range of clinical phenotypes, including diabetes mellitus and neurodegeneration. Inheritance patterns of pathogenic variants of this gene can be autosomal recessive or dominant, and differences in penetrance present challenges for accurate diagnosis and genetic counselling.MethodsThree probands and one elder brother from three families were systematically evaluated and the clinical data of other family members were collected from the medical history. Whole-exome sequencing was performed on the probands, and RNA sequencing was performed on four patients, their parents with WFS1 variants, and four gender- and age-matched children with type 1 diabetes mellitus.ResultsThere were six patients with diabetes. Dilated cardiomyopathy, a rare manifestation of WFS1-related disease, was identified in one patient, along with MRI findings of brain atrophy at age 7 years and 3 months, the earliest age of discovery we know of. Whole-exome sequencing revealed five pathogenic or likely pathogenic variants in the WFS1 gene, including c.1348dupC (p.His450Profs*93), c.1381A>C (p.Thr461pro), c.1329C>G (p.Ser443Arg), c.2081delA (p.Glu694Glyfs*16), c.1350-1356delinsGCA (p.His450Glnfs*26), of which 3 variants (c.1348dupC, c.2081delA, c.1350-1356delinsGCA) were novel that have not been previously reported. The differentially expressed genes were mainly associated with immune-related pathways according to the Gene Ontology enrichment analysis of the RNA sequencing data. The exon 1 region of HLA-DRB1 in two patients was not transcribed, while the transcription of the region in their parents was normal.ConclusionThis study emphasizes the clinical and genetic heterogeneity in patients, even in the same family with WFS1 variants. MRI evaluation of the brain should be considered when WFS1-related disorder is first diagnosed.

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“…It is rare to have different clinical phenotypes in the same family with WFS1 variants, which are complex and limited by a lack of functional studies establishing the impact of the variants on protein function. Only one prior study has described the presence of autosomal dominant and recessive forms of WFS1-related diseases within the same family 27 . The observations in probands (patients 35 and 36) and their family members support the lack of genotype-phenotype correlation in complex WFS1 variants.…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic analysis in a Chinese cohort of children and adolescents with diabetes/persistent hyperglycemia

Ding

Niu

Lou

et al. 2020

J of Diabetes Invest

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Aims/Introduction: To investigate the genetic etiology and evaluate the diagnostic application of next-generation sequencing for diabetes/persistent hyperglycemia in children and adolescents. Materials and Methods: Patients with diabetes/persistent hyperglycemia, presenting with at least one other clinical manifestation (other than diabetes) or with a family history of diabetes, were recruited. The clinical and laboratory characteristics of the patients were recorded. Next-generation sequencing was carried out, and candidate variants were verified by Sanger sequencing. Variant pathogenicity was further evaluated according to the American College of Medical Genetics and Genomics guidelines. Results: This study included 101 potential probands, 36 of whom were identified as positive by genetic testing. A further 51.2 and 20.9% of variants were determined to be pathogenic or likely pathogenic, respectively. Variants associated with the disease were primarily identified in 21 genes and three regions of copy number variants. Among the 39 variants in 21 genes, 61.5% (24/39) were novel. The genetic diagnosis of 23 patients was confirmed based on genetic evidence and associated clinical manifestations. We reported GCK variants (21.7%, 5/23) as the most common etiology in our cohort. Different clinical manifestations were observed in one family with WFS1 variants. Conclusions: Our findings support the use of next-generation sequencing as a standard method in patients with diabetes/persistent hyperglycemia and provide insights into the etiologies of these conditions.

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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

Cited by 9 publications

References 12 publications

Efficacy of GLP-1 Agonist Therapy in Autosomal Dominant WFS1-Related Disorder: A Case Report

Efficacy of GLP-1 Agonist Therapy in Autosomal Dominant WFS1-Related Disorder: A Case Report

Complex clinical manifestations and new insights in RNA sequencing of children with diabetes and WFS1 variants

Clinical and genetic analysis in a Chinese cohort of children and adolescents with diabetes/persistent hyperglycemia

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