Fine mapping of autosomal dominant nonsyndromic hearing impairment <i>DFNA21</i> to chromosome 6p24.1‐22.3

Brouwer, Arjan P.M. de; Kunst, H.P.M.; Krebsová, Alice; Asseldonk, Karin van; Reis, André; Snoeckx, R.L.; Camp, Guy Van; Cremers, C.W.R.J.; Cremers, Frans P.M.; Kremer, Hannie

doi:10.1002/ajmg.a.30844

Cited by 5 publications

(5 citation statements)

References 34 publications

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“…Segregation analysis identified the RIPOR2 variant in 20 of 23 affected subjects of family W97-056 (Figure 1). The variant was not found in subjects III:14, III:20, and III:21; a recombination event in subject III:14 previously delimited the centromeric border of the DFNA21 locus (10). The RIPOR2 c.1696_1707del variant was also found in three unaffected family members (V:2, age 23 years; IV:26, age 40 years and III:28, age 51 years).…”

Section: Exome Sequencing Revealed An In-frame Deletion In Ripor2mentioning

confidence: 89%

“…It affects a highly conserved protein region of RIPOR2 (Rho family-interacting cell polarization regulator 2) which is present in all RIPOR2 isoforms (Supplemental Figure 2). RIPOR2 has previously been associated with recessively inherited early-onset hearing loss and is positioned 0.9 Mb centromeric of the DFNA21 locus (10,14). No copy number variants (CNVs) were detected that were shared by all three subjects.…”

Section: Exome Sequencing Revealed An In-frame Deletion In Ripor2mentioning

confidence: 99%

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ARIPOR2in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss

et al. 2020

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BackgroundHearing loss is one of the most prevalent disabilities worldwide, and has a significant impact on quality of life. The adult-onset type of the condition is highly heritable but the genetic causes are largely unknown, which is in contrast to childhood-onset hearing loss.MethodsFamily and cohort studies included exome sequencing and characterisation of the hearing phenotype. Ex vivo protein expression addressed the functional effect of a DNA variant.ResultsAn in-frame deletion of 12 nucleotides in RIPOR2 was identified as a highly penetrant cause of adult-onset progressive hearing loss that segregated as an autosomal dominant trait in 12 families from the Netherlands. Hearing loss associated with the deletion in 63 subjects displayed variable audiometric characteristics and an average (SD) age of onset of 30.6 (14.9) years (range 0–70 years). A functional effect of the RIPOR2 variant was demonstrated by aberrant localisation of the mutant RIPOR2 in the stereocilia of cochlear hair cells and failure to rescue morphological defects in RIPOR2-deficient hair cells, in contrast to the wild-type protein. Strikingly, the RIPOR2 variant is present in 18 of 22 952 individuals not selected for hearing loss in the Southeast Netherlands.ConclusionCollectively, the presented data demonstrate that an inherited form of adult-onset hearing loss is relatively common, with potentially thousands of individuals at risk in the Netherlands and beyond, which makes it an attractive target for developing a (genetic) therapy.

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Section: Exome Sequencing Revealed An In-frame Deletion In Ripor2mentioning

confidence: 89%

Section: Exome Sequencing Revealed An In-frame Deletion In Ripor2mentioning

confidence: 99%

ARIPOR2in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss

et al. 2020

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“…In 2020, a heterozygous Dutch founder RIPOR2 in‐frame deletion, p.Gln566_Lys569del, affecting a highly conserved region, was associated with a very variable NSSNHL with a range of onset from congenital to 70 years and normal vestibular tests (DFNA21) 6,13,14 …”

Section: Discussionmentioning

confidence: 99%

“…In 2020, a heterozygous Dutch founder RIPOR2 in-frame deletion, p.Gln566_Lys569del, affecting a highly conserved region, was associated with a very variable NSSNHL with a range of onset from congenital to 70 years and normal vestibular tests (DFNA21). 6,13,14 In mouse cochlea, RIPOR2 is specifically localized to the base of the stereocilia. 5 Ripor2 knockout (KO) mice are deaf at 4 weeks of age due to impaired mechanotransduction 15 and morphological defects of hair bundle polarity, cohesion and length of stereocilia were observed.…”

Section: Zebrafishmentioning

confidence: 99%

RIPOR2: A new gene of non‐syndromic cochleovestibular dysfunction, discrepancy between human pathology and animal models

Morel,

Ernest,

Serey‐Gaut

et al. 2023

Clinical Genetics

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Cochleovestibular dysfunctions are rare conditions misrecognized. A homozygous pathogenic variation c.1561C > T (p.Arg521*) in RIPOR2 (RHO family interacting cell polarization regulator 2) has been identified by WES in Tunisian siblings suffering from congenital bilateral profound hearing and vestibular dysfunctions. In contrast to the vestibular areflexia observed in our patients, deaf Ripor2 KO mouse model and our zebrafish model have normal vestibular function.

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“…DFNA21 (9,10). However, the underlying pathogenic variant in the studied family (W97-056) remained elusive.…”

Section: Introductionmentioning

confidence: 99%

ARIPOR2in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss

Smits

Liu

Lanting

et al. 2019

Preprint

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Hearing loss is one of the most prevalent disabilities worldwide, and has a significant impact on quality of life. The adult-onset type of the condition is highly heritable but the genetic causes are largely unknown, which is in contrast to childhood-onset hearing loss. We identified an in-frame deletion of 12 nucleotides in RIPOR2 as a highly penetrant cause of adult-onset progressive hearing loss that segregated as an autosomal dominant trait in 12 families from the Netherlands. Hearing loss associated with the deletion in 63 subjects displayed variable audiometric characteristics and an average age of onset of 30.6 years (SD 14.9 years, range 0-70 years). A functional effect of the RIPOR2 variant was demonstrated by aberrant localization of the mutant RIPOR2 in the stereocilia of cochlear hair cells and failure to rescue morphological defects in RIPOR2-deficient hair cells, in contrast to the wildtype protein. Strikingly, the RIPOR2 variant is present in 18 of 22,952 individuals not selected for hearing loss in the Southeast Netherlands. Collectively, these data demonstrate that an inherited form of adult-onset hearing loss is relatively common, with potentially thousands of individuals at risk in the Netherlands and beyond, which makes it an attractive target for developing a (genetic) therapy.

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Fine mapping of autosomal dominant nonsyndromic hearing impairment DFNA21 to chromosome 6p24.1‐22.3

Cited by 5 publications

References 34 publications

ARIPOR2in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss

ARIPOR2in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss

RIPOR2: A new gene of non‐syndromic cochleovestibular dysfunction, discrepancy between human pathology and animal models

ARIPOR2in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss

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