Ashfaque Ahmed1, Meng Wang1, Rizwan Khan1, Abid Ali Shah1, Hui Guo1, Sajid Malik2, Kun Xia3, Zhengmao Hu4,5. 1. Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, Hunan, China. 2. Human Genetics Program, Department of Zoology, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, Pakistan. malik@qau.edu.pk. 3. Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, Hunan, China. xiakun@sklmg.edu.cn. 4. Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, Hunan, China. huzhengmao@sklmg.edu.cn. 5. Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha, 410078, Hunan, China. huzhengmao@sklmg.edu.cn.
Abstract
BACKGROUND: Hearing loss/deafness is a common otological disorder found in the Pakistani population due to the high prevalence of consanguineous unions, but the full range of genetic causes is still unknown. METHODS: A large consanguineous Pakistani kindred with hearing loss was studied. Whole-exome sequencing and Sanger sequencing were performed to search for the candidate gene underlying the disease phenotype. A minigene assay and reverse transcription polymerase chain reaction was used to assess the effect of splicing variants. RESULTS: The splicing variants of OTOF (NM_194248, c.3289-1G>T) cosegregated with the disease phenotype in this Pakistani family. The substitution of a single base pair causes the deletion of 10 bp (splicing variant 1) or 13 bp (splicing variant 2) from exon 27, which results in truncated proteins of 1141 and 1140 amino acids, respectively. CONCLUSION: Our findings reveal an OTOF splice-site variant as pathogenic for profound hearing loss in this family.
BACKGROUND: Hearing loss/deafness is a common otological disorder found in the Pakistani population due to the high prevalence of consanguineous unions, but the full range of genetic causes is still unknown. METHODS: A large consanguineous Pakistani kindred with hearing loss was studied. Whole-exome sequencing and Sanger sequencing were performed to search for the candidate gene underlying the disease phenotype. A minigene assay and reverse transcription polymerase chain reaction was used to assess the effect of splicing variants. RESULTS: The splicing variants of OTOF (NM_194248, c.3289-1G>T) cosegregated with the disease phenotype in this Pakistani family. The substitution of a single base pair causes the deletion of 10 bp (splicing variant 1) or 13 bp (splicing variant 2) from exon 27, which results in truncated proteins of 1141 and 1140 amino acids, respectively. CONCLUSION: Our findings reveal an OTOF splice-site variant as pathogenic for profound hearing loss in this family.
Entities:
Keywords:
Hearing loss; Minigene; OTOF; Splice acceptor site
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