Abstract
PurposeThe aim of this study was to determine the genetic cause of autosomal dominant nonsyndromic hearing loss segregating in a multigenerational family.MethodsClinical examination, genome-wide linkage analysis, and exome sequencing were carried out on the family.ResultsAffected individuals presented with early-onset progressive mild hearing impairment with a fairly flat, gently downsloping or U-shaped audiogram configuration. Detailed clinical examination excluded any additional symptoms. Linkage analysis detected an interval on chromosome 1p21 with a logarithm of the odds (LOD) score of 8.29: designated locus DFNA37. Exome sequencing identified a novel canonical acceptor splice-site variant c.652-2A>C in the COL11A1 gene within the DFNA37 locus. Genotyping of all 48 family members confirmed segregation of this variant with the deafness phenotype in the extended family. The c.652-2A>C variant is novel, highly conserved, and confirmed in vitro to alter RNA splicing.ConclusionWe have identified COL11A1 as the gene responsible for deafness at the DFNA37 locus. Previously, COL11A1 was solely associated with Marshall and Stickler syndromes. This study expands its phenotypic spectrum to include nonsyndromic deafness. The implications of this discovery are valuable in the clinical diagnosis, prognosis, and treatment of patients with COL11A1 pathogenic variants.
Highlights
Hereditary hearing loss is a genetically heterogeneous disorder with over 150 genes implicated
Mirroring the genetic complexity is the breadth of phenotypic manifestations associated with pathogenic variants in these genes as more than 20% exhibit an extraordinary pleiotropy: they can give rise to either autosomal dominant nonsyndromic hearing loss (ADNSHL) or autosomal recessive nonsyndromic hearing loss (ARNSHL) (e.g., TECTA and TMC1) and they can cause syndromic hearing loss or nonsyndromic hearing loss (NSHL) (e.g., Usher type 1–causing genes, WFS1, TBC1D24, and COLL11A2)
We present a novel splice-site altering variant in COL11A1 that segregates in a large family with postlingual progressive ADNSHL and expands the phenotypic spectrum of pathogenic variants in COL11A1
Summary
Hereditary hearing loss is a genetically heterogeneous disorder with over 150 genes implicated. The collagen family is diverse and consists of more than 20 genetically distinct genes. Collagens are fibrous structural proteins involved in the construction of skin, cartilage, bone, eye, and other tissues.[7,8] All collagen molecules are comprised of three α-chain subunits tightly wrapped into a triple helix. The composition of each triple helix either contains one, two, or three different types of α-chains. The α-chains encoded by COL11A1, COL11A2, and COL2A1 comprise a unique collagen fibril that is essential for proper skeletal and cartilage formation as well as ocular and auditory function.[6,9,10]
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