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). 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. 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. 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.

Thashi Bharadwaj

Anushree Acharya

Fati Ullah Khan

Saadullah Khan

Irfan Ullah

Isabelle Schrauwen

Wasim Ahmad

Suzanne M. Leal

BMC Medical Genomics

BMC MEDICAL GENOMICS 是一本开放获取期刊，在功能基因组学、基因组结构、基因组规模人口遗传学、表观基因组学、蛋白质组学、系统分析和与人类健康和疾病相关的药物基因组学等各个方面发表原创的同行评审研究文章。

BMC Medical Genomics is an open-access journal that publishes original peer-reviewed research articles across various aspects of functional genomics, genomic structure, population genetics at a genomic scale, epigenomics, proteomics, systems analysis, and pharmacogenomics related to human health and disease.

BMC Medical Genomics 是一本开放获取的期刊，专注于功能基因组学、基因组结构、基因组规模的人口遗传学、表观基因组学、蛋白质组学、系统分析以及与人类健康和疾病相关的药物基因组学等领域，发表原创的同行评审研究文章。

Category	Quartile
医学	4
医学, 遗传学	4

THBS1 is a new autosomal recessive non-syndromic hearing impairment gene

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Journal Info

Category	Quartile
GENETICS & HEREDITY	3