THBS1 is a new autosomal recessive non-syndromic hearing impairment gene
Abstract Background Prelingual hearing impairment (HI) is genetically highly heterogenous. Early diagnosis and intervention are essential for psychosocial development. In this study we investigated a consanguineous family from Pakistan with autosomal recessive (AR) non-syndromic sensorineural HI (NS...
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BMC
2024-12-01
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| Series: | BMC Medical Genomics |
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| Online Access: | https://doi.org/10.1186/s12920-024-02060-w |
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| author | Thashi Bharadwaj Anushree Acharya Fati Ullah Khan Saadullah Khan Irfan Ullah Isabelle Schrauwen Wasim Ahmad Suzanne M. Leal |
| author_facet | Thashi Bharadwaj Anushree Acharya Fati Ullah Khan Saadullah Khan Irfan Ullah Isabelle Schrauwen Wasim Ahmad Suzanne M. Leal |
| author_sort | Thashi Bharadwaj |
| collection | DOAJ |
| description | Abstract Background Prelingual hearing impairment (HI) is genetically highly heterogenous. Early diagnosis and intervention are essential for psychosocial development. In this study we investigated a consanguineous family from Pakistan with autosomal recessive (AR) non-syndromic sensorineural HI (NSHI). Methods A DNA sample from an HI member of a consanguineous Pakistani family segregating ARNSHL underwent exome sequencing. Using Sanger sequencing select variants were validated and tested for segregation using DNA samples from additional family members. We further investigated RNA expression data for the candidate gene in mouse and human inner ear and human inner ear organoids using data obtained from the gene Expression Analysis Resource. Results We identified thrombospondin 1 (THBS1) as a new NSHI gene. A homozygous frameshift variant [c.1470del: p.(Ile491Serfs*45)] was observed in the three hearing-impaired and in the heterozygous state in three unaffected family members. Unlike for most ARNSHI, hearing-impaired individuals had audiograms with a sloping pattern, showing more pronounced HI in the mid and high frequencies (ranging from moderate to profound) compared to the low frequencies. RNA expression data indicates THBS1 is expressed during human inner ear development. Additionally, THBS1 is expressed in the cochlear epithelium and supporting cells of the mouse inner ear during embryonic and postnatal stages. Previously, THBS1 was demonstrated to affect hearing in knockout mice by influencing the formation and function of afferent synapses in the inner ear. Conclusions Our findings highlight THBS1 as a potential novel candidate gene for human HI characterized by a sloping high-frequency audio profile. This discovery enhances our understanding of the genetic etiology of HI and will aid in advancing molecular diagnosis. |
| format | Article |
| id | doaj-art-84d50ec2ee0f465c9fe8633c54dbc0e1 |
| institution | Kabale University |
| issn | 1755-8794 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
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| series | BMC Medical Genomics |
| spelling | doaj-art-84d50ec2ee0f465c9fe8633c54dbc0e12024-12-22T12:54:01ZengBMCBMC Medical Genomics1755-87942024-12-011711710.1186/s12920-024-02060-wTHBS1 is a new autosomal recessive non-syndromic hearing impairment geneThashi Bharadwaj0Anushree Acharya1Fati Ullah Khan2Saadullah Khan3Irfan Ullah4Isabelle Schrauwen5Wasim Ahmad6Suzanne M. Leal7Center for Statistical Genetics, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Medical CenterCenter for Statistical Genetics, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Medical CenterDepartment of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam UniversityDepartment of Biotechnology and Genetic Engineering, Kohat University of Science & Technology (KUST)Department of Chemistry, Shaheed Benazir Bhutto UniversityCenter for Statistical Genetics, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Medical CenterDepartment of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam UniversityCenter for Statistical Genetics, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Medical CenterAbstract Background Prelingual hearing impairment (HI) is genetically highly heterogenous. Early diagnosis and intervention are essential for psychosocial development. In this study we investigated a consanguineous family from Pakistan with autosomal recessive (AR) non-syndromic sensorineural HI (NSHI). Methods A DNA sample from an HI member of a consanguineous Pakistani family segregating ARNSHL underwent exome sequencing. Using Sanger sequencing select variants were validated and tested for segregation using DNA samples from additional family members. We further investigated RNA expression data for the candidate gene in mouse and human inner ear and human inner ear organoids using data obtained from the gene Expression Analysis Resource. Results We identified thrombospondin 1 (THBS1) as a new NSHI gene. A homozygous frameshift variant [c.1470del: p.(Ile491Serfs*45)] was observed in the three hearing-impaired and in the heterozygous state in three unaffected family members. Unlike for most ARNSHI, hearing-impaired individuals had audiograms with a sloping pattern, showing more pronounced HI in the mid and high frequencies (ranging from moderate to profound) compared to the low frequencies. RNA expression data indicates THBS1 is expressed during human inner ear development. Additionally, THBS1 is expressed in the cochlear epithelium and supporting cells of the mouse inner ear during embryonic and postnatal stages. Previously, THBS1 was demonstrated to affect hearing in knockout mice by influencing the formation and function of afferent synapses in the inner ear. Conclusions Our findings highlight THBS1 as a potential novel candidate gene for human HI characterized by a sloping high-frequency audio profile. This discovery enhances our understanding of the genetic etiology of HI and will aid in advancing molecular diagnosis.https://doi.org/10.1186/s12920-024-02060-wAutosomal recessive non-syndromic hearing impairmentConsanguinityExome sequencingInner earThrombospondinTHBS1 |
| spellingShingle | Thashi Bharadwaj Anushree Acharya Fati Ullah Khan Saadullah Khan Irfan Ullah Isabelle Schrauwen Wasim Ahmad Suzanne M. Leal THBS1 is a new autosomal recessive non-syndromic hearing impairment gene BMC Medical Genomics Autosomal recessive non-syndromic hearing impairment Consanguinity Exome sequencing Inner ear Thrombospondin THBS1 |
| title | THBS1 is a new autosomal recessive non-syndromic hearing impairment gene |
| title_full | THBS1 is a new autosomal recessive non-syndromic hearing impairment gene |
| title_fullStr | THBS1 is a new autosomal recessive non-syndromic hearing impairment gene |
| title_full_unstemmed | THBS1 is a new autosomal recessive non-syndromic hearing impairment gene |
| title_short | THBS1 is a new autosomal recessive non-syndromic hearing impairment gene |
| title_sort | thbs1 is a new autosomal recessive non syndromic hearing impairment gene |
| topic | Autosomal recessive non-syndromic hearing impairment Consanguinity Exome sequencing Inner ear Thrombospondin THBS1 |
| url | https://doi.org/10.1186/s12920-024-02060-w |
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