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Whole exome sequencing identified mutations causing hearing loss in five consanguineous Pakistani families.

ABSTRACT: BACKGROUND:Hearing loss is the most common sensory defect, and it affects over 6% of the population worldwide. Approximately 50-60% of hearing loss patients are attributed to genetic causes. Currently, more than 100 genes have been reported to cause non-syndromic hearing loss. It is possible and efficient to screen all potential disease-causing genes for hereditary hearing loss by whole exome sequencing (WES). METHODS:We collected 5 consanguineous pedigrees from Pakistan with hearing loss and applied WES in selected patients for each pedigree, followed by bioinformatics analysis and Sanger validation to identify the causal genes. RESULTS:Variants in 7 genes were identified and validated in these pedigrees. We identified single candidate variant for 3 pedigrees: GIPC3 (c.937?T?>?C), LOXHD1 (c.6136G?>?A) and TMPRSS3 (c.941?T?>?C). The remaining 2 pedigrees each contained two candidate variants: TECTA (c.4045G?>?A) and MYO15A (c.3310G?>?T and c.9913G?>?C) for one pedigree and DFNB59 (c.494G?>?A) and TRIOBP (c.1952C?>?T) for the other pedigree. The candidate variants were validated in all available samples by Sanger sequencing. CONCLUSION:The candidate variants in hearing-loss genes were validated to be co-segregated in the pedigrees, and they may indicate the aetiologies of hearing loss in such patients. We also suggest that WES may be a suitable strategy for hearing-loss gene screening in clinical detection.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC7368710 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Whole exome sequencing identified mutations causing hearing loss in five consanguineous Pakistani families.

Zhou Yingjie Y Tariq Muhammad M He Sijie S Abdullah Uzma U Zhang Jianguo J Baig Shahid Mahmood SM

BMC medical genetics 20200718 1

<h4>Background</h4>Hearing loss is the most common sensory defect, and it affects over 6% of the population worldwide. Approximately 50-60% of hearing loss patients are attributed to genetic causes. Currently, more than 100 genes have been reported to cause non-syndromic hearing loss. It is possible and efficient to screen all potential disease-causing genes for hereditary hearing loss by whole exome sequencing (WES).<h4>Methods</h4>We collected 5 consanguineous pedigrees from Pakistan with hear ...[more]

PMID: 32682410

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Project description:PurposeThis study was conducted to localize and identify causal mutations associated with autosomal recessive retinitis pigmentosa (RP) in consanguineous familial cases of Pakistani origin.MethodsOphthalmic examinations that included funduscopy and electroretinography (ERG) were performed to confirm the affectation status. Blood samples were collected from all participating individuals, and genomic DNA was extracted. A genome-wide scan was performed, and two-point logarithm of odds (LOD) scores were calculated. Sanger sequencing was performed to identify the causative variants. Subsequently, we performed whole exome sequencing to rule out the possibility of a second causal variant within the linkage interval. Sequence conservation was performed with alignment analyses of PDE6A orthologs, and in silico splicing analysis was completed with Human Splicing Finder version 2.4.1.ResultsA large multigenerational consanguineous family diagnosed with early-onset RP was ascertained. An ophthalmic clinical examination consisting of fundus photography and electroretinography confirmed the diagnosis of RP. A genome-wide scan was performed, and suggestive two-point LOD scores were observed with markers on chromosome 5q. Haplotype analyses identified the region; however, the region did not segregate with the disease phenotype in the family. Subsequently, we performed a second genome-wide scan that excluded the entire genome except the chromosome 5q region harboring PDE6A. Next-generation whole exome sequencing identified a splice acceptor site mutation in intron 16: c.2028-1G>A, which was completely conserved in PDE6A orthologs and was absent in ethnically matched 350 control chromosomes, the 1000 Genomes database, and the NHLBI Exome Sequencing Project. Subsequently, we investigated our entire cohort of RP familial cases and identified a second family who harbored a splice acceptor site mutation in intron 10: c.1408-2A>G. In silico analysis suggested that these mutations will result in the elimination of wild-type splice acceptor sites that would result in either skipping of the respective exon or the creation of a new cryptic splice acceptor site; both possibilities would result in retinal photoreceptor cells that lack PDE6A wild-type protein.Conclusionswe report two splice acceptor site variations in PDE6A in consanguineous Pakistani families who manifested cardinal symptoms of RP. Taken together with our previously published work, our data suggest that mutations in PDE6A account for about 2% of the total genetic load of RP in our cohort and possibly in the Pakistani population as well.

Dataset Information

Whole exome sequencing identified mutations causing hearing loss in five consanguineous Pakistani families.

Publications

Whole exome sequencing identified mutations causing hearing loss in five consanguineous Pakistani families.

Similar Datasets

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