Reevaluating the splice-altering variant in TECTA as a cause of nonsyndromic hearing loss DFNA8/12 by functional analysis of RNA

Author:

Yang Yan1ORCID,Luo Haiyan1,Pan Lijuan23,Feng Chuanxin1,Guo Zhen1,Zou Yongyi1,Zeng Baitao1,Huang Shuhui1,Yuan Huizhen1,Wu Ping45,Liu Danping1,Dan Yi1,Xiao Junfang1,Li XinYu1,Chen ZhongFa1,Zeng Xiao Ni6,Jiang XiangLong7,Yang Bicheng1,Liu Yuhe89,Liu Yanqiu1ORCID

Affiliation:

1. Jiangxi Key Laboratory of Birth Defect Prevention and Control, Jiangxi Maternal and Child Health Hospital, No. 508, Xizhan Street, Honggutan District, Nanchang City, Jiangxi Province , 330006 , China

2. Department of Obstetrics , Xiangya Hospital, , No. 87, Xiangya Road, Kaifu District, Changsha City, Hunan Province, 410083 , China

3. Central South University , Xiangya Hospital, , No. 87, Xiangya Road, Kaifu District, Changsha City, Hunan Province, 410083 , China

4. Department of Otolaryngology , Head and Neck Surgery, , No. 566, University Avenue Road, Honggutan District, Nanchang City, Jiangxi Province, 330006 , China

5. The Second Affiliated Hospital of Nanchang University , Head and Neck Surgery, , No. 566, University Avenue Road, Honggutan District, Nanchang City, Jiangxi Province, 330006 , China

6. Department of Neurology, The First Affiliated Hospital of Nanchang University , No. 17, Yongwai Zhengjie Road, Donghu District, Nanchang City, Jiangxi Province, 330006 , China

7. Nan Chang Reproductive Hospital , No. 198, Jinggangshan Avenue Road, Qingyun Pu District, Nanchang City, Jiangxi Province Nanchang, 330006 , China

8. Department of Otolaryngology , Head and Neck Surgery, Beijing Friendship Hospital, , No. 95 Yongan Road, Xicheng District, Beijing, 100050 , China

9. Capital Medical University , Head and Neck Surgery, Beijing Friendship Hospital, , No. 95 Yongan Road, Xicheng District, Beijing, 100050 , China

Abstract

Abstract Purpose The aim of this study was to determine the genetic cause of early onset autosomal dominant hearing loss segregating in five-generation kindred of Chinese descent and provide preimplantation genetic testing (PGT)for them. Methods Clinical examination, pedigree analysis and exome sequencing were carried out on the family. Minigene-based splicing analysis, in vivo RNA analysis and protein structure prediction by molecular modeling were conducted on the candidate variant. PGT for the causative variation and chromosome aneuploidis based on SNP analysis has been used for avoidance of hearing loss in this family. Results All the affected individuals presented with moderate down-sloping hearing loss and whole-exome sequencing identified a novel splice-site variant c.5383+6T>A in the tested subjects within the TECTA locus. Genotyping of all the 32 family members confirmed segregation of this variant and the hearing loss phenotype in the extended family. Functional analysis of RNA and molecular modeling indicates that c.5383+6T>A is a pathogenic splice-site variant and should be considered as genetic cause of the hearing loss. Furthermore, a successful singleton pregnancy with no variation in TECTA c.5383+6 was established and a healthy male child was born by PGT. Conclusion We have identified a novel variant c.5383+6T>A in TECTA ZA-ZP inter-domain, which could be attributable to the early-onset autosomal dominant hearing loss. The implications of our study are valuable in elucidating the disrupted RNA splicing and uncovering the genetic cause of hearing loss with TECTA pathogenic variants, as well as providing reproductive approaches to healthy offspring.

Funder

Provincial Health Commission Program of Jiangxi

Key Research and Development Program of Jiangxi Province

Nature Science Research Project of Jiangxi

Jiangxi Provincial Administration of Traditional Chinese Medicine Program of Jiangxi

Jiangxi Province Key Research and Development Project

Publisher

Oxford University Press (OUP)

Reference39 articles.

1. Human nonsyndromic sensorineural deafness;Friedman;Annu Rev Genomics Hum Genet,2003

2. Clinical evaluation and etiologic diagnosis of hearing loss: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG);Li;Genet Med,2022

3. Hereditary non-syndromic sensorineural hearing loss: transforming silence to sound;Schrijver;J Mol Diagn,2004

4. Evidence for digenic inheritance of nonsyndromic hereditary hearing loss in a Swedish family;Balciuniene;Am J Hum Genet,1998

5. A gene for autosomal dominant nonsyndromic hearing loss (DFNA12) maps to chromosome 11q22-24;Verhoeven;Am J Hum Genet,1997

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