Variable degrees of hearing impairment in a Dutch DFNX4 (DFN6) family

Weegerink, N.J.D.; Huygen, P.L.M.; Schraders, Margit; Kremer, Hannie; Pennings, Ronald J.E.; Kunst, H.P.M.

doi:10.1016/j.heares.2011.08.010

Cited by 16 publications

(18 citation statements)

References 21 publications

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“…Among them, a careful attention should be directed to SMPX gene whose mutations have been recently reported to lead to a mild bilateral HL phenotype in females and a severe to profound early-onset HL in the affected males (Niu et al, 2017). Alternatively, as in the case of our family, the mother shows a monolateral severe to profound (sky-slope) HL while the proband displays a post-lingual bilateral symmetric severe to profound medium-high frequencies NSHL, as described in only one case worldwide (Weegerink et al, 2011). For this reason, during genetic counseling, it would be very important to carefully verify the monolateral clinical manifestations in affected females as an indicator of an X-linked form of HL.…”

Section: Discussionmentioning

confidence: 53%

Genomic Studies in a Large Cohort of Hearing Impaired Italian Patients Revealed Several New Alleles, a Rare Case of Uniparental Disomy (UPD) and the Importance to Search for Copy Number Variations

et al. 2018

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Hereditary hearing loss (HHL) is a common disorder characterized by a huge genetic heterogeneity. The definition of a correct molecular diagnosis is essential for proper genetic counseling, recurrence risk estimation, and therapeutic options. From 20 to 40% of patients carry mutations in GJB2 gene, thus, in more than half of cases it is necessary to look for causative variants in the other genes so far identified (~100). In this light, the use of next-generation sequencing technologies has proved to be the best solution for mutational screening, even though it is not always conclusive. Here we describe a combined approach, based on targeted re-sequencing (TRS) of 96 HHL genes followed by high-density SNP arrays, aimed at the identification of the molecular causes of non-syndromic HHL (NSHL). This strategy has been applied to study 103 Italian unrelated cases, negative for mutations in GJB2, and led to the characterization of 31% of them (i.e., 37% of familial and 26.3% of sporadic cases). In particular, TRS revealed TECTA and ACTG1 genes as major players in the Italian population. Furthermore, two de novo missense variants in ACTG1 have been identified and investigated through protein modeling and molecular dynamics simulations, confirming their likely pathogenic effect. Among the selected patients analyzed by SNP arrays (negative to TRS, or with a single variant in a recessive gene) a molecular diagnosis was reached in ~36% of cases, highlighting the importance to look for large insertions/deletions. Moreover, copy number variants analysis led to the identification of the first case of uniparental disomy involving LOXHD1 gene. Overall, taking into account the contribution of GJB2, plus the results from TRS and SNP arrays, it was possible to reach a molecular diagnosis in ~51% of NSHL cases. These data proved the usefulness of a combined approach for the analysis of NSHL and for the definition of the epidemiological picture of HHL in the Italian population.

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Section: Discussionmentioning

confidence: 53%

Genomic Studies in a Large Cohort of Hearing Impaired Italian Patients Revealed Several New Alleles, a Rare Case of Uniparental Disomy (UPD) and the Importance to Search for Copy Number Variations

et al. 2018

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“…The age of onset is usually prelingual, with a rapid decline beginning in the first decade of life, a male phenotype profile that has been reported in a Dutch family with a different SMPX mutation. On the other hand, females carrying an SMPX mutation exhibit significant intra-and interfamily variability Weegerink et al, 2011). In our DFNX4 families, the female carriers of the SMPX mutation may be normal hearing, or hearing impaired, with intrafamily variations in the onset, progression, and severity of the auditory phenotype (see Figures 3 and 5).…”

Section: Dfnx4: Smpx Genementioning

confidence: 95%

“…The most common X-linked phenotype is the congenital mixed hearing loss associated with POU3F4, a gene causing increased intracochlear pressure, stapes fixation, and temporal bone anomalies, with the danger of perilymphatic gusher and sudden deafness when middle ear surgery is attempted (de Kok et al, 1995). Other hearing disorders, such as those caused by mutations in the SMPX gene, involve early mild and emergent forms of hearing loss, with a significant risk of delayed detection and intervention Weegerink et al, 2011).…”

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confidence: 99%

X-Linked Hearing Loss: Two Gene Mutation Examples Provide Generalizable Implications for Clinical Care

et al. 2014

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The study shows how this unique inheritance pattern and both gender and mutation-specific phenotype variations can alert audiologists to the presence of X-linked genetic etiologies in their clinical practice. By incorporating this knowledge into clinical decision making, audiologists can facilitate the early identification of X-linked hearing loss and contribute to the effective team management of affected families.

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“…The phenotype of the SMPX c.99delC carriers is similar to the phenotype of SMPX mutations carriers previously reported. [Huebner et al, ; Schraders et al, ; Weegerink et al, ] For example, males in previous studies of SMPX presented early, around 2 years of age, with bilateral slowly progressive hearing loss, whereas females with the same mutations showed a wide range of variability in the onset and severity of the disease much like that of the subjects observed in Families 2024 and 2196.…”

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confidence: 94%

A Novel Deletion inSMPXCauses a Rare form of X-Linked Progressive Hearing Loss in Two Families Due to a Founder Effect

et al. 2012

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X-linked hearing loss is the rarest form of genetic hearing loss contributing to <1% of cases. We identified a multiplex family from Newfoundland (Family 2024) segregating X-linked hearing loss. Haplotyping of the X chromosome and sequencing of positional candidate genes revealed a novel point deletion (c.99delC) in SMPX which encodes a small muscle protein responsible for reducing mechanical stress during muscle contraction. This novel deletion causes a frameshift and a premature stop codon (p.Arg34GlufsX47). We successfully sequenced both SMPX wild-type and mutant alleles from cDNA of a lymphoblastoid cell line, suggesting that the mutant allele may not be degraded via nonsense-mediated mRNA decay. To investigate the role of SMPX in other subpopulations, we fully sequenced SMPX in 229 Canadian probands with hearing loss and identified a second Newfoundland Family (2196) with the same mutation, and a shared haplotype on the X chromosome, suggesting a common ancestor.

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Variable degrees of hearing impairment in a Dutch DFNX4 (DFN6) family

Cited by 16 publications

References 21 publications

Genomic Studies in a Large Cohort of Hearing Impaired Italian Patients Revealed Several New Alleles, a Rare Case of Uniparental Disomy (UPD) and the Importance to Search for Copy Number Variations

Genomic Studies in a Large Cohort of Hearing Impaired Italian Patients Revealed Several New Alleles, a Rare Case of Uniparental Disomy (UPD) and the Importance to Search for Copy Number Variations

X-Linked Hearing Loss: Two Gene Mutation Examples Provide Generalizable Implications for Clinical Care

A Novel Deletion inSMPXCauses a Rare form of X-Linked Progressive Hearing Loss in Two Families Due to a Founder Effect

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