A Frameshift Variant in ANKRD24 Implicates Its Role in Human Non‐Syndromic Hearing Loss

ABSTRACT Hearing loss (HL) is the most prevalent sensorineural disorders, affecting about one in 1000 newborns. Over half of the cases are attributed to genetic factors; however, due to the extensive clinical and genetic heterogeneity, many cases remain without a conclusive genetic diagnosis. The ad...

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Veröffentlicht in:Clinical genetics 2025-02, Vol.107 (2), p.214-218
Hauptverfasser: Kazemi, Negar, Rezvani Rezvandeh, Raziye, Zare Ashrafi, Farzane, Shokouhian, Ebrahim, Edizadeh, Masoud, Booth, Kevin T. A., Kahrizi, Kimia, Najmabadi, Hossein, Mohseni, Marzieh
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container_issue 2
container_start_page 214
container_title Clinical genetics
container_volume 107
creator Kazemi, Negar
Rezvani Rezvandeh, Raziye
Zare Ashrafi, Farzane
Shokouhian, Ebrahim
Edizadeh, Masoud
Booth, Kevin T. A.
Kahrizi, Kimia
Najmabadi, Hossein
Mohseni, Marzieh
description ABSTRACT Hearing loss (HL) is the most prevalent sensorineural disorders, affecting about one in 1000 newborns. Over half of the cases are attributed to genetic factors; however, due to the extensive clinical and genetic heterogeneity, many cases remain without a conclusive genetic diagnosis. The advent of next‐generation sequencing methodologies in recent years has greatly helped unravel the genetic etiology of HL by identifying numerous genes and causative variants. Despite this, much remains to be uncovered about the genetic basis of sensorineural hearing loss (SNHL). Here, we report an Iranian consanguineous family with postlingual, moderate‐to‐severe autosomal recessive SNHL. After first excluding plausible variants in known deafness‐causing genes using whole exome sequencing, we reanalyzed the data, using a gene/variant prioritization pipeline established for novel gene discovery for HL. This approach identified a novel homozygous frameshift variant c.1934_1937del; (p.Thr645Lysfs*52) in ANKRD24, which segregated with the HL phenotype in the family. Recently, ANKRD24 has been shown to be a pivotal constituent of the stereocilia rootlet in cochlea hair cells and interacts with TRIOBP, a protein already implicated in human deafness. Our data implicate for the first time, ANKRD24 in human nonsyndromic HL (NSHL) and expands the genetic spectrum of HL. This case report identified a homozygous frameshift variant of ANKRD24 as a novel gene associated with nonsyndromic hearing loss (NHSL) in a consanguineous Iranian family. ANKRD24 is expressed in the stereocilia rootlets in inner ear hair cells, and the encoded protein interacts with TRIOBP, which is a known deafness‐causing gene.
doi_str_mv 10.1111/cge.14635
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The advent of next‐generation sequencing methodologies in recent years has greatly helped unravel the genetic etiology of HL by identifying numerous genes and causative variants. Despite this, much remains to be uncovered about the genetic basis of sensorineural hearing loss (SNHL). Here, we report an Iranian consanguineous family with postlingual, moderate‐to‐severe autosomal recessive SNHL. After first excluding plausible variants in known deafness‐causing genes using whole exome sequencing, we reanalyzed the data, using a gene/variant prioritization pipeline established for novel gene discovery for HL. This approach identified a novel homozygous frameshift variant c.1934_1937del; (p.Thr645Lysfs*52) in ANKRD24, which segregated with the HL phenotype in the family. Recently, ANKRD24 has been shown to be a pivotal constituent of the stereocilia rootlet in cochlea hair cells and interacts with TRIOBP, a protein already implicated in human deafness. Our data implicate for the first time, ANKRD24 in human nonsyndromic HL (NSHL) and expands the genetic spectrum of HL. This case report identified a homozygous frameshift variant of ANKRD24 as a novel gene associated with nonsyndromic hearing loss (NHSL) in a consanguineous Iranian family. ANKRD24 is expressed in the stereocilia rootlets in inner ear hair cells, and the encoded protein interacts with TRIOBP, which is a known deafness‐causing gene.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>39434538</pmid><doi>10.1111/cge.14635</doi><tpages>5</tpages><orcidid>https://orcid.org/0000-0002-6587-7706</orcidid><orcidid>https://orcid.org/0000-0003-1200-4044</orcidid><orcidid>https://orcid.org/0000-0002-6084-7778</orcidid><orcidid>https://orcid.org/0000-0001-9139-9632</orcidid></addata></record>
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subjects ANKRD24
Child
Cochlea
Consanguinity
Deafness
Exome Sequencing
Female
Frameshift Mutation - genetics
Genes
Genetic factors
Genetic Predisposition to Disease
Genetic screening
Hair cells
Hearing loss
Hearing Loss, Sensorineural - genetics
Hearing Loss, Sensorineural - pathology
High-Throughput Nucleotide Sequencing
Homozygote
Humans
Iran
Male
Neonates
non‐syndromic hearing loss
novel gene
Pedigree
Phenotype
Phenotypes
whole exome sequencing
Whole genome sequencing
title A Frameshift Variant in ANKRD24 Implicates Its Role in Human Non‐Syndromic Hearing Loss
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