WFS1 mutations in hearing-impaired children

Häkli, Sanna; Kytövuori, Laura; Luotonen, Mirja; Sorri, Martti; Majamaa, Kari

doi:10.3109/14992027.2014.887230

Cited by 9 publications

(6 citation statements)

References 25 publications

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“…The rare homozygous variant, p. Gly674Arg, in the WFS1 gene was observed in an individual with Arab ethnicity who was apparently normal (unlikely to be related to Wolfram syndrome). The variant is considered to be pathogenic/likely pathogenic (Khanim, Kirk, Latif, & Barrett, ) but our data support the idea that this variant is polymorphism in the homozygous state and it can be considered to be causative only when occurring in trans with other variants in the WFS1 gene (Häkli, Kytövuori, Luotonen, Sorri, & Majamaa, ). This variant should also be reclassified as of uncertain significance in its homozygous state.…”

Section: Resultssupporting

confidence: 63%

“…normal (unlikely to be related to Wolfram syndrome). The variant is considered to be pathogenic/likely pathogenic (Khanim, Kirk, Latif, & Barrett, 2001) but our data support the idea that this variant is polymorphism in the homozygous state and it can be considered to be causative only when occurring in trans with other variants in the WFS1 gene (Häkli, Kytövuori, Luotonen, Sorri, & Majamaa, 2014).…”

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confidence: 66%

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Iranome: A catalog of genomic variations in the Iranian population

et al. 2019

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Considering the application of human genome variation databases in precision medicine, population‐specific genome projects are continuously being developed. However, the Middle Eastern population is underrepresented in current databases. Accordingly, we established Iranome database (http://www.iranome.com) by performing whole exome sequencing on 800 individuals from eight major Iranian ethnic groups representing the second largest population of Middle East. We identified 1,575,702 variants of which 308,311 were novel (19.6%). Also, by presenting higher frequency for 37,384 novel or known rare variants, Iranome database can improve the power of molecular diagnosis. Moreover, attainable clinical information makes this database a good resource for classifying pathogenicity of rare variants. Principal components analysis indicated that, apart from Iranian‐Baluchs, Iranian‐Turkmen, and Iranian‐Persian Gulf Islanders, who form their own clusters, rest of the population were genetically linked, forming a super‐population. Furthermore, only 0.6% of novel variants showed counterparts in “Greater Middle East Variome Project”, emphasizing the value of Iranome at national level by releasing a comprehensive catalog of Iranian genomic variations and also filling another gap in the catalog of human genome variations at international level. We introduce Iranome as a resource which may also be applicable in other countries located in neighboring regions historically called Greater Iran (Persia).

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Section: Resultssupporting

confidence: 63%

supporting

confidence: 66%

Iranome: A catalog of genomic variations in the Iranian population

et al. 2019

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“…The family history, clinical, and biochemical features of the six patients who were identified as positive after NGS for a variant of uncertain significance (VUS), likely pathogenic or pathogenic, were reported. A summary is presented in Table 1 [ 15 , 16 , 17 , 18 , 19 , 20 ]. Six other patients showed benign or likely benign variants after NGS analysis, and sixteen showed a negative result.…”

Section: Resultsmentioning

confidence: 99%

Next Generation Sequencing Analysis of MODY-X Patients: A Case Report Series

Maltoni

Franceschi

Natale

et al. 2022

JPM

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Background: Classic criteria for a maturity-onset diabetes of the young (MODY) diagnosis are often unable to identify all subjects, and traditional Sanger sequencing, using a candidate gene approach, leads to a high prevalence of missed genetic diagnosis, classified as MODY-X. Next generation sequencing (NGS) panels provide a highly sensitive method even for rare forms. Methods: We investigated 28 pediatric subjects suspected for MODY-X, utilizing a 15-gene NGS panel for monogenic diabetes (MD). Results: NGS detected variants of uncertain significance (VUS), likely pathogenic or pathogenic for rarer subtypes of MODY, in six patients. We found variants in the wolframin gene (WFS1), traditionally not considered in MD genetic screening panels, in three patients; KCNJ11 gene mutation, typically responsible for neonatal diabetes and rarely causing isolated diabetes in adolescents; INS gene mutation; a variant in the HNF1B gene in a young male with diabetes on sulfonylurea treatment. Conclusion: In our cohort, the availability of an NGS panel for MD was determined for the correct identification of MD subtypes in six patients with MODY-X. Our study underlines how a precise diagnosis utilizing NGS may have an impact on the management of different forms of MODY and, thus, lead to a tailored treatment and enable genetic counselling of other family members.

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“…Besides, two additional heterozygous mutations have also previously been reported in a de novo state. One WFS1 pathogenic variant p.G831S (c.2492G>A) was found in a Finland sporadic case with NSHL and another p.H313Y (c.937C>T) mutation was shared by two unrelated Danish sporadic patients with WLS (Hakli, Kytovuori, Luotonen, Sorri, & Majamaa, 2014; Hansen et al., 2005). To our knowledge, together with our present study, there are only four de novo mutations in WFS1 reported in different racial backgrounds from Asian, European, and US/Caucasian ancestries (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Recurrent de novo WFS1 pathogenic variants in Chinese sporadic patients with nonsyndromic sensorineural hearing loss

Guan

Wang

Lan

et al. 2020

Molec Gen & Gen Med

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Background Hereditary hearing loss (HL) is heterogeneous in terms of their phenotypic features, modes of inheritance, and causative gene mutations. The contribution of genetic variants to sporadic HL remains largely expanding. Either recessive or de novo dominant variants could result in an apparently sporadic occurrence of HL. In an attempt to find such variants we recruited 128 Chinese patients with sporadic nonsyndromic sensorineural HL (NSHL) and performed targeted deafness multigene sequencing in these unrelated trios‐families to elucidate the molecular basis. Methods We analyzed a total of 384 available members (probands and their two parents) from 128 unrelated Chinese families presenting with bilateral sensorineural HL, in which previous screening had found no mutations with the GJB2 , SLC26A4 , and MT‐RNR1 genes. We used a targeted genomic enrichment platform to simultaneously capture exons, splicing sites, and immediate flanking intron sequences of 127 known deafness genes. Sanger sequencing was used to identify probands and their two parents segregating causative variants in the candidate gene. Results We observed that two heterozygous de novo WFS1 mutations in exon 8: c.2051C>T (p.A684V) and c.2590G>A (p.E864K) in five families. The two de novo WFS1 mutations were found in 3.9% (5/128) of sporadic HL patients. We found that four of the five patients had the same de novo p.A684V mutation, and their audiograms showed symmetrical bilateral and profound sensorineural hearing impairments at all frequencies, but only the proband with de novo p.E864K mutation demonstrated significantly bilateral moderate low–mid frequency sensorineural HL. Our data suggest that this WFS1 p.A684V is likely to be a de novo mutational hot spot. Conclusions We found 3.9% (5/128) of sporadic NSHL is caused by de novo WFS1 mutations. Our data provide that the de novo p.E864K mutation is first identified and de novo p.A684V mutation is likely to be a mutational hot spot in WFS1 . It is the first study to highlight that WFS1 gene with the two de novo mutations has been indicated to classify the distinct hearing impairment phenotypes. Furthermore, de novo p.A684V serves as a WFS1 mutational hot spot that was found in the Chinese population with sporadic childhood NSHL, and our study also provides pointers toward the necessity for sequencing of asymptomatic parents of a sporadic case with an apparent dominant pathogenic variant.

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WFS1 mutations in hearing-impaired children

Abstract: WFS1 gene mutations are a rare cause of HI among Finnish children with HI.

Cited by 9 publications

References 25 publications

Iranome: A catalog of genomic variations in the Iranian population

Iranome: A catalog of genomic variations in the Iranian population

Next Generation Sequencing Analysis of MODY-X Patients: A Case Report Series

Recurrent de novo WFS1 pathogenic variants in Chinese sporadic patients with nonsyndromic sensorineural hearing loss

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