1. Whole exome sequencing, in silico and functional studies confirm the association of the GJB2 mutation p.Cys169Tyr with deafness and suggest a role for the TMEM59 gene in the hearing process
- Author
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Mona Mahfood, Rania Harati, Jihen Chouchen, Abdullah Al Mutery, Walaa Kamal Eddine Ahmad Mohamed, and Abdelaziz Tlili
- Subjects
0106 biological sciences ,0301 basic medicine ,RFLP, restriction fragment length polymorphism ,SAM, Sequence Alignment/Map ,BWA, Burrows-Wheeler Aligner ,01 natural sciences ,ARNSHL, autosomal recessive non-syndromic hearing loss ,Non-syndromic hearing loss ,NSHL, Non-syndromic hearing loss ,Missense mutation ,BAM, Binary Alignment Map ,VariMAT, Variation and Mutation Annotation Toolkit ,Biology (General) ,RT-qPCR, quantitative reverse transcription PCR ,Exome sequencing ,KCNQ3, Potassium Voltage-Gated Channel Subfamily Q Member 3 ,Genetics ,WES, Whole exome sequencing ,ST3GAL1, ST3 Beta-Galactoside Alpha-2,3-Sialyltransferase 1 ,Mutation (genetic algorithm) ,gnomAD, genome aggregation database ,Original Article ,medicine.symptom ,General Agricultural and Biological Sciences ,GJB2, Gap Junction Protein Beta 2 ,gEAR, gene Expression Analysis Resource ,Hearing loss ,QH301-705.5 ,In silico ,Biology ,SJL, Swiss Jim Lambert ,DNA sequencing ,SPATA13, Spermatogenesis Associated 13 ,HL, Hearing loss ,03 medical and health sciences ,PROVEAN, Protein Variation Effect Analyzer ,UAE, United Arab Emirates ,medicine ,otorhinolaryngologic diseases ,dpSNP, Single Nucleotide Polymorphism Database ,Gene ,Genetic heterogeneity ,C1QTNF9, C1q and TNF related 9 ,Whole exome sequencing ,SIFT, Sorting Intolerant From Tolerant ,NGS, next generation sequencing ,PolyPhen-2, Polymorphism Phenotyping v2 ,TMEM59, Transmembrane Protein 59 ,RT-PCR, reverse transcription PCR ,030104 developmental biology ,HHLA1, HERV-H LTR-Associating 1 ,Cx26, Connexin 26 ,qPCR, quantitative PCR ,ESRRAP2, Estrogen-Related Receptor Alpha Pseudogene 2 ,ROH, runs of homozygosity ,010606 plant biology & botany ,GJB2 gene ,Actb, Actin beta - Abstract
The development of next generation sequencing techniques has facilitated the detection of mutations at an unprecedented rate. These efficient tools have been particularly beneficial for extremely heterogeneous disorders such as autosomal recessive non-syndromic hearing loss, the most common form of genetic deafness. GJB2 mutations are the most common cause of hereditary hearing loss. Amongst them the NM_004004.5: c.506G > A (p.Cys169Tyr) mutation has been associated with varying severity of hearing loss with unclear segregation patterns. In this study, we report a large consanguineous Emirati family with severe to profound hearing loss fully segregating the GJB2 missense mutation p.Cys169Tyr. Whole exome sequencing (WES), in silico, splicing and expression analyses ruled out the implication of any other variants and confirmed the implication of the p.Cys169Tyr mutation in this deafness family. We also show preliminary murine expression analysis that suggests a link between the TMEM59 gene and the hearing process. The present study improves our understanding of the molecular pathogenesis of hearing loss. It also emphasizes the significance of combining next generation sequencing approaches and segregation analyses especially in the diagnosis of disorders characterized by complex genetic heterogeneity.
- Published
- 2021