Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37.
Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37.
复制标题
DOI：
10.1038/s41436-018-0285-0
复制
发表时间：
2019-04
期刊：
影响因子：
--
通讯作者：
Smith SD
中科院分区：
文献类型：
--
作者：
Booth KT;Askew JW;Talebizadeh Z;Huygen PLM;Eudy J;Kenyon J;Hoover D;Hildebrand MS;Smith KR;Bahlo M;Kimberling WJ;Smith RJH;Azaiez H;Smith SD
本研究的目的是确定常染色体显性遗传性非综合征性听力损失分离的多代家庭的遗传原因。对该家系进行了临床检查、全基因组连锁分析和外显子组测序。受影响的个人表现为早发性进行性轻度听力障碍，听力图结构相当平坦，轻轻向下倾斜或U形。详细的临床检查排除了任何其他症状。连锁分析检测到染色体1 p21上的区间，对数的优势（LOD）得分为8.29：指定的基因座DFNA 37。外显子组测序鉴定了DFNA 37基因座内COL 11 A1基因中的一种新的典型受体剪接位点变体c.652-2A>C。所有48个家族成员的基因分型证实了该变异体在大家族中与耳聋表型的分离。c.652-2A>C变异体是一种新的、高度保守的变异体，并在体外被证实可以改变RNA剪接。我们已经确定COL 11 A1是DFNA 37位点上导致耳聋的基因。以前，COL 11 A1仅与马歇尔和Stickler综合征相关。这项研究扩大了其表型谱，包括非综合征性耳聋。这一发现的意义是有价值的临床诊断，预后和治疗患者的COL 11 A1致病性变异。
The aim of this study was to determine the genetic cause of autosomal dominant nonsyndromic hearing loss segregating in a multigenerational family. Clinical examination, genome-wide linkage analysis, and exome sequencing were carried out on the family. Affected 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. We 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.