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Rare-variant association analysis reveals known and new age-related hearing loss genes

EUROPEAN JOURNAL OF HUMAN GENETICS 2023年第6期31卷 638-647页

作者： Cornejo-Sanchez, Diana M. Li, Guangyou Fabiha, Tabassum Wang, Ran Acharya, Anushree Everard, Jenna L. Kadlubowska, Magda K. Huang, Yin schrauwen, isabelle Wang, Gao T. DeWan, Andrew T. Leal, Suzanne M. Columbia Univ Ctr Stat Genet Gertrude H Sergievsky Ctr Med Ctr New York NY 10032 USA Columbia Univ Dept Neurol New York NY 10032 USA Yale Sch Publ Hlth Dept Chron Dis Epidemiol New Haven CT USA Yale Sch Publ Hlth Ctr Perinatal Pediat & Environm Epidemiol New Haven CT USA Columbia Univ Taub Inst Alzheimers Dis & Aging Brain Med Ctr New York NY 10032 USA

Age-related (AR) hearing loss (HL) is a prevalent sensory deficit in the elderly population. Several studies showed that common variants increase ARHL susceptibility. Here, we demonstrate that rare-variants play a crucial role in ARHL etiology. We analyzed exome and imputed data from white-European UK Biobank volunteers, performing both single-variant and rare-variant aggregate association analyses using self-reported ARHL phenotypes. We identified and replicated associations between ARHL and rare-variants in KLHDC7B, PDCD6, MYO6, SYNJ2, and TECTA. PUS7L and EYA4 also revealed rare-variant associations with ARHL. EYA4, MYO6, and TECTA are all known to underline Mendelian nonsyndromic HL. PDCD6, a new HL gene, plays an important role in apoptosis and has widespread inner ear expression, particularly in the inner hair cells. An unreplicated common variant association was previously observed for KHLDC7B, here we demonstrate that rare-variants in this gene also play a role in ARHL etiology. Additionally, the first replicated association between SYNJ2 and ARHL was detected. Analysis of common variants revealed several previously reported, i.e., ARHGEF28, and new, i.e., PIK3R3, ARHL associations, as well as ones we replicate here for the first time, i.e., BAIAP2L2, CRIP3, KLHDC7B, MAST2, and SLC22A7. It was also observed that the odds ratios for rare-variant ARHL associations, were higher than those for common variants. In conclusion, we demonstrate the vital role rare-variants, including those in Mendelian nonsyndromic HL genes, play in the etiology of ARHL.

关键词： Genetics research Genome-wide association studies

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A novel autosomal dominant GREB1L variant associated with non-syndromic hearing impairment in Ghana

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BMC MEDICAL GENOMICS 2022年第1期15卷 1-10页

作者： Adadey, Samuel Mawuli Aboagye, Elvis Twumasi Esoh, Kevin Acharya, Anushree Bharadwaj, Thashi Lin, Nicole S. Amenga-Etego, Lucas Awandare, Gordon A. schrauwen, isabelle Leal, Suzanne M. Wonkam, Ambroise Univ Ghana West African Ctr Cell Biol Infect Pathogens WACCB LG 54 Accra Ghana Univ Cape Town Fac Hlth Sci Div Human Genet ZA-7925 Cape Town South Africa Columbia Univ Ctr Stat Genet Sergievsky Ctr Dept NeurolMed Ctr New York NY 10032 USA Columbia Univ Taub Inst Alzheimers Dis & Aging Brain Med Ctr New York NY 10032 USA Johns Hopkins Univ McKusick Nathans Inst Dept Genet Med Sch Med Baltimore MD 21205 USA

Background Childhood hearing impairment (HI) is genetically heterogeneous with many implicated genes, however, only a few of these genes are reported in African populations. Methods This study used exome and Sanger sequencing to resolve the possible genetic cause of non-syndromic HI in a Ghanaian family. Results We identified a novel variant c.3041G > A: p.(Gly1014Glu) in GREB1L (DFNA80) in the index case. The GREB1L: p.(Gly1014Glu) variant had a CADD score of 26.5 and was absent from human genomic databases such as TopMed and gnomAD. In silico homology protein modeling approaches displayed major structural differences between the wildtype and mutant proteins. Additionally, the variant was predicted to probably affect the secondary protein structure that may impact its function. Publicly available expression data shows a higher expression of Greb1L in the inner ear of mice during development and a reduced expression in adulthood, underscoring its importance in the development of the inner ear structures. Conclusion This report on an African individual supports the association of GREB1L variant with non-syndromic HI and extended the evidence of the implication of GREB1L variants in HI in diverse populations.

关键词： Hearing impairment GREB1L Ghana

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A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis

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HUMAN GENETICS 2022年第3-4期141卷 951-963页

作者： Hojland, Allan Thomas Tavernier, Lisse J. M. schrauwen, isabelle Sommen, Manou Topsakal, Vedat Schatteman, isabelle Dhooge, Ingeborg Huber, Alex Zanetti, Diego Kunst, Henricus P. M. Hoischen, Alexander Petersen, Michael B. Van Camp, Guy Fransen, Erik Aalborg Univ Dept Clin Med Aalborg Denmark Aalborg Univ Hosp Dept Clin Genet Res & Knowledge Ctr Sensory Genet Aalborg Denmark Univ Antwerp Ctr Med Genet Antwerp Belgium Antwerp Univ Hosp Antwerp Belgium Columbia Univ Gertrude H Sergievsky Ctr Ctr Stat Genet Dept NeurolMed Ctr New York NY 10027 USA Univ Antwerp Dept ORL & Head & Neck Surg Antwerp Univ Hosp Edegem Belgium St Augustinus Hosp Antwerp European Inst ORL Antwerp Belgium Ghent Univ Hosp Dept Otolaryngol Ghent Belgium Univ Hosp Zurich Dept Otorhinolaryngol Head & Neck Surg Zurich Switzerland Univ Milan Dept Clin Sci & Community Hlth Audiol Unit IRCCS Fdn Ca GrandaOsple Maggiore Policlin Milan Italy Radboud Univ Nijmegen Med Ctr Radboud Inst Hlth Sci Dept Otorhinolaryngol Nijmegen Netherlands Maastricht Univ Med Ctr Dept Otorhinolaryngol Maastricht Netherlands Radboud Univ Nijmegen Med Ctr Dept Human Genet Nijmegen Netherlands Radboud Univ Nijmegen Med Ctr Dept Otorhinolaryngol Hearing & Genes Nijmegen Netherlands Radboud Univ Nijmegen Med Ctr Dept Internal Med Nijmegen Netherlands Radboud Univ Nijmegen Med Ctr Radboud Ctr Infect Dis RCI Nijmegen Netherlands Univ Antwerp StatUa Ctr Stat Antwerp Belgium

In this study, we investigated the association of ACAN variants with otosclerosis, a frequent cause of hearing loss among young adults. We sequenced the coding, 5 '-UTR and 3 '-UTR regions of ACAN in 1497 unrelated otosclerosis cases and 1437 matched controls from six different subpopulations. The association between variants in ACAN and the disease risk was tested through single variant and gene-based association tests. After correction for multiple testing, 14 variants were significantly associated with otosclerosis, ten of which represented independent association signals. Eight variants showed a consistent association across all subpopulations. Allelic odds ratios of the variants identified four predisposing and ten protective variants. Gene-based tests showed an association of very rare variants in the 3 '-UTR with the phenotype. The associated exonic variants are all located in the CS domain of ACAN and include both protective and predisposing variants with a broad spectrum of effect sizes and population frequencies. This includes variants with strong effect size and low frequency, typical for monogenic diseases, to low effect size variants with high frequency, characteristic for common complex traits. This single-gene allelic spectrum with both protective and predisposing alleles is unique in the field of complex diseases. In conclusion, these findings are a significant advancement to the understanding of the etiology of otosclerosis.

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Genomic analysis of childhood hearing loss in the Yoruba population of Nigeria

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EUROPEAN JOURNAL OF HUMAN GENETICS 2022年第1期30卷 42-52页

作者： Adeyemo, Adebolajo Faridi, Rabia Chattaraj, Parna Yousaf, Rizwan Tona, Risa Okorie, Samuel Bharadwaj, Thashi Nouel-Saied, Liz M. Acharya, Anushree schrauwen, isabelle Morell, Robert J. Leal, Suzanne M. Friedman, Thomas B. Griffith, Andrew J. Roux, isabelle Univ Ibadan Coll Med Inst Child Hlth Ibadan Nigeria NIDCD Lab Mol Genet NIH Bethesda MD 20892 USA NIDCD Otolaryngol Branch NIH Bethesda MD 20892 USA Columbia Univ Ctr Stat Genet Gertrude H Sergievsky Ctr Dept NeurolMed Ctr 630 168th St New York NY 10032 USA NIDCD Genom & Computat Biol Core NIH Bethesda MD 20892 USA Columbia Univ Taub Inst Alzheimers Dis & Aging Brain Med Ctr 630 W 168th St New York NY 10032 USA Univ Tennessee Coll Med Dept Otolaryngol Hlth Sci Ctr 910 Madison Ave Memphis TN 38163 USA

Although variant alleles of hundreds of genes are associated with sensorineural deafness in children, the genes and alleles involved remain largely unknown in the Sub-Saharan regions of Africa. We ascertained 56 small families mainly of Yoruba ethno-lingual ancestry in or near Ibadan, Nigeria, that had at least one individual with nonsyndromic, severe-to-profound, prelingual-onset, bilateral hearing loss not attributed to nongenetic factors. We performed a combination of exome and Sanger sequencing analyses to evaluate both nuclear and mitochondrial genomes. No biallelic pathogenic variants were identified in GJB2, a common cause of deafness in many populations. Potential causative variants were identified in genes associated with nonsyndromic hearing loss (CIB2, COL11A1, ILDR1, MYO15A, TMPRSS3, and WFS1), nonsyndromic hearing loss or Usher syndrome (CDH23, MYO7A, PCDH15, and USH2A), and other syndromic forms of hearing loss (CHD7, OPA1, and SPTLC1). Several rare mitochondrial variants, including m.1555A>G, were detected in the gene MT-RNR1 but not in control Yoruba samples. Overall, 20 (33%) of 60 independent cases of hearing loss in this cohort of families were associated with likely causal variants in genes reported to underlie deafness in other populations. None of these likely causal variants were present in more than one family, most were detected as compound heterozygotes, and 77% had not been previously associated with hearing loss. These results indicate an unusually high level of genetic heterogeneity of hearing loss in Ibadan, Nigeria and point to challenges for molecular genetic screening, counseling, and early intervention in this population.

关键词： Genetics research Medical genomics Biomedicine general Human Genetics Bioinformatics Gene Expression Cytogenetics

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Clinical, muscle imaging, and genetic characteristics of dystrophinopathies with deep-intronic DMD variants

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JOURNAL OF NEUROLOGY 2023年第2期270卷 925-937页

作者： Xie, Zhiying Sun, Chengyue Liu, Chang Xie, Zhihao Wei, Luhua Yu, Jiaxi Ling, Chen Guo, Xuejun Liu, Yilin Yu, Meng Leng, Yinglin Meng, Lingchao Sun, Yunchuang Deng, Jianwen Leal, Suzanne M. schrauwen, isabelle Wang, Zhaoxia Yuan, Yun Peking Univ First Hosp Dept Neurol 8 Xishiku St Beijing 100034 Peoples R China Peking Univ Peoples Hosp Dept Neurol Beijing 100044 Peoples R China Sichuan Univ West China Sch Publ Hlth Dept Epidemiol & Biostat Chengdu 610041 Peoples R China Sichuan Univ West China Fourth Hosp Chengdu 610041 Peoples R China Beijing Jishuitan Hosp Dept Neurol Beijing 100035 Peoples R China Peking Union Med Coll Hosp Dept Pathol Beijing 100730 Peoples R China Columbia Univ Ctr Stat Genet Med Ctr Dept NeurolSergievsky Ctr New York NY USA

Background Phenotypic heterogeneity within or between families with a same deep-intronic splice-altering variant in the DMD gene has never been systematically analyzed. This study aimed to determine the phenotypic and genetic characteristics of patients with deep-intronic DMD variants. Methods Of 1338 male patients with a suspected dystrophinopathy, 38 were confirmed to have atypical pathogenic DMD variants via our comprehensive genetic testing approach. Of the 38 patients, 30 patients from 22 unrelated families with deep-intronic DMD variants underwent a detailed clinical and imaging assessment. Results Nineteen different deep-intronic DMD variants were identified in the 30 patients, including 15 with Duchenne muscular dystrophy (DMD), 14 with Becker muscular dystrophy (BMD), and one with X-linked dilated cardiomyopathy. Of the 19 variants, 15 were single-nucleotide variants, 2 were structural variants (SVs), and 2 were pure-intronic large-scale SVs causing aberrant inclusion of other protein-coding genes sequences into the mature DMD transcripts. The trefoil with single fruit sign was observed in 18 patients and the concentric fatty infiltration pattern was observed in 2 patients. Remarkable phenotypic heterogeneity was observed not only in skeletal but also cardiac muscle involvement in 2 families harboring a same deep-intronic variant. Different skeletal muscle involvement between families with a same variant was observed in 4 families. High inter-individual phenotypic heterogeneity was observed within two BMD families and one DMD family. Conclusions Our study first highlights the variable phenotypic expressivity of deep-intronic DMD variants and demonstrates a new class of deep-intronic DMD variants, i.e., pure-intronic SVs involving other protein-coding genes.

关键词： Dystrophinopathies Deep-intronic variants Aberrant splicing Phenotypic heterogeneity Muscle imaging

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A Novel Variant in VPS13B Underlying Cohen Syndrome

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BIOMED RESEARCH INTERNATIONAL 2023年第1期2023卷 9993801页

作者： Hussain, Abrar Acharya, Anushree Bharadwaj, Thashi Leal, Suzanne Khaliq, Abdul Mir, Asif schrauwen, isabelle Int Islamic Univ Fac Basic & Appl Sci Dept Biol Sci Human Mol Genet Lab Islamabad 44000 Pakistan Columbia Univ Ctr Stat Genet Gertrude H Sergievsky Ctr Dept NeurolMed Ctr New York NY 10032 USA Univ Washington Dept Genome Sci Seattle WA 98195 USA Columbia Univ Taub Inst Alzheimers Dis & Aging Brain Med Ctr New York NY 10032 USA Columbia Univ Med Ctr Dept Neurol New York NY 10032 USA

Pathogenic variants in vacuolar protein sorting 13 homolog B (VPS13B) cause Cohen syndrome (CS), a clinically diverse neurodevelopmental disorder. We used whole exome and Sanger sequencing to identify disease-causing variants in a Pakistani family with intellectual disability, microcephaly, facial dysmorphism, neutropenia, truncal obesity, speech delay, motor delay, and insomnia. We identified a novel homozygous nonsense variant c.8841G > A: p.(W2947*) in VPS13B (NM_017890.5) which segregated with the disease. Sleep disturbances are commonly seen in neurodevelopmental disorders and can exacerbate medical issues if left untreated. We demonstrate that individuals with Cohen syndrome may also be affected by sleep disturbances. In conclusion, we expand the genetic and phenotypic features of Cohen syndrome in the Pakistani population.

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Variants in EFCAB7 underlie nonsyndromic postaxial polydactyly

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EUROPEAN JOURNAL OF HUMAN GENETICS 2023年第11期31卷 1270-1274页

作者： Bilal, Muhammad Khan, Hammal Khan, Muhammad Javed Haack, Tobias B. Buchert, Rebecca Liaqat, Khurram Ullah, Kifayat Ahmed, Sohail Bharadwaj, Thashi Acharya, Anushree Peralta, Susana Najumuddin Ali, Hamid Hasni, Muhammad Sharif schrauwen, isabelle Ullah, Asmat Ahmad, Wasim Leal, Suzanne M. Quaid I Azam Univ Fac Biol Sci Dept Biochem Islamabad Pakistan COMSATS Univ Islamabad Dept Biosci Islamabad Pakistan Columbia Univ Ctr Stat Genet Gertrude H Sergievsky Ctr Med Ctr New York NY USA Univ Balochistan Inst Biochem Quetta Pakistan Univ Tubingen Inst Med Genet & Appl Genom Tubingen Germany Quaid I Azam Univ Natl Ctr Bioinformat Islamabad Pakistan Univ Copenhagen Novo Nord Fdn Ctr Basic Metab Res Fac Hlth & Med Sci Copenhagen Denmark Columbia Univ Med Ctr Taub Inst Res Alzheimers Dis & Aging Brain New York NY 10033 USA

Polydactyly is the most common limb malformation that occurs in 1.6-10.6 per one thousand live births, with incidence varying with ancestry. The underlying gene has been identified for many of the similar to 100 syndromes that include polydactyly. While for the more common form, nonsydromic polydactyly, eleven candidate genes have been reported. We investigated the underlying genetic cause of autosomal recessive nonsyndromic postaxial polydactyly in four consanguineous Pakistani families. Some family members with postaxial polydactyly also present with syndactyly, camptodactyly, or clinodactyly. Analysis of the exome sequence data revealed two novel homozygous frameshift deletions in EFCAB7: [c.830delG;p.(Gly277Valfs*5)];in three families and [c.1350_1351delGA;p.(Asn451Phefs*2)] in one family. Sanger sequencing confirmed that these variants segregated with postaxial polydactyly, i.e., family members with postaxial polydactyly were found to be homozygous while unaffected members were heterozygous or wild type. EFCAB7 displays expressions in the skeletal muscle and on the cellular level in cilia. IQCE-EFCAB7 and EVC-EVC2 are part of the heterotetramer EvC complex, which is a positive regulator of the Hedgehog (Hh) pathway, that plays a key role in limb formation. Depletion of either EFCAB7 or IQCE inhibits induction of Gli1, a direct Hh target gene. Variants in IQCE and GLI1 have been shown to cause nonsyndromic postaxial polydactyly, while variants in EVC and EVC2 underlie Ellis van Creveld and Weyers syndromes, which include postaxial polydactyly as a phenotype. This is the first report of the involvement of EFCAB7 in human disease etiology.

关键词： Bone Consanguinity Medical genetics

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Exome sequencing revealed a novel homozygous variant in TRMT61 A in a multiplex family with atypical Cornelia de Lange Syndrome from Rwanda

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BMC Medical Genomics 2025年第1期18卷 1-9页

作者： Uwibambe, Esther Yalcouyé, Abdoulaye Aboagye, Elvis Twumasi Xhakaza, Lettilia Popel, Kalinka Dukuze, Norbert Bharadwaj, Thashi de Kock, Carmen schrauwen, isabelle Leal, Suzanne M. Mutesa, Leon Wonkam, Ambroise Center for Human Genetics College of Medicine and Health Sciences University of Rwanda Kigali Rwanda Division of Human Genetics Department of Medicine Faculty of Health Sciences University of Cape Town Cape Town South Africa Mckusick Nathans Institute and Department of Genetic Medicine Johns Hopkins University School of Medicine Baltimore 21205 MD United States Center for Statistical Genetics Gertrude H. Sergievsky Center and Department of Neurology Columbia University Medical Center New York NY United States Department of Translational Neurosciences University of Arizona College of Medicine –Phoenix Phoenix 85004 AZ United States Taub Institute for Alzheimer’s Disease and the Aging Brain Columbia University Medical Center New York NY United States

Background: In 30% of patients who exhibit the clinical profile of Cornelia de Lange Syndrome (CdLS), the genetic cause remains undetermined. This proportion tends to be higher in low-resource settings including Africa. We performed a molecular characterization of CdLS in a multiplex Rwandan family. Methods: After a clinical evaluation of two affected siblings, DNA isolated from peripheral whole blood of the affected patients and their parents underwent Exome Sequencing (ES). Sanger sequencing validated the variant segregating with CdLS. In silico predictive tools, protein modelling, and cell-based experiments using HEK293T cells were used to investigate the pathogenicity of the variant found. Results: We identified a family with two parents and their two offspring (male and female), who were referred for hearing impairment. The 17-year-old female presented bilateral profound hearing impairment with moderate hypertelorism, progressive visual impairment, and secondary amenorrhea. The 14-year-old male displayed intellectual disability and a bilateral profound hearing impairment with no noticeable facial dysmorphism. Following exome sequencing (ES) of DNA samples obtained from the four family members, we found that the siblings harbored a novel likely pathogenic homozygous missense variant in the TRMT61 A gene [NM_152307.3:c.665C > T p.(Ala222Val)] inherited from both heterozygous parents. In silico analysis suggested that the variant substitutes a highly conserved amino acid, and 2-D structure modelling revealed a significant decrease in the stability of the protein. Cell-based experiment in HEK293T showed that the variant significantly affected the TRMT61 A protein localization which is thought to impact the mitochondrial and cytosolic functions. Conclusion: We reported a novel biallelic variant in TRMT61 A, [NM_152307.3:c.665C > T p.(Ala222Val)], which is associated with autosomal recessive atypical CdLS in a multiplex Rwandan family, the first report from Africa, a

关键词： Cornelia de Lange Syndrome TRMT61 A Whole exome sequencing

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Novel variants in the RDH5 Gene in a Chinese Han family with fundus albipunctatus

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BMC OPHTHALMOLOGY 2022年第1期22卷 69-69页

作者： Qian, Tianwei Gong, Qiaoyun Shen, Hangqi Li, Caihua Wang, Gao Xu, Xun schrauwen, isabelle Wang, Weijun Shanghai Jiao Tong Univ Shanghai Gen Hosp Dept Ophthalmol 100 Haining Rd Shanghai 200080 Peoples R China Natl Clin Res Ctr Eye Dis Shanghai Peoples R China Shanghai Key Lab Ocular Fundus Dis Shanghai Peoples R China Shanghai Engn Ctr Visual Sci & Photomed Shanghai Peoples R China Shanghai Engn Ctr Precise Diag & Treatment Eye Di Shanghai Peoples R China Columbia Univ Dept Neurol Med Ctr 630W 168th St New York NY 10032 USA Genesky Biotechnol Inc Shanghai Peoples R China

Background The aim of this study is to identify the genetic defects in a Chinese family with fundus albipunctatus. Methods Complete ophthalmic examinations, including slit-lamp biomicroscopy, dilated indirect ophthalmoscopy, fundus photography, autofluorescence, swept source optical coherence tomography (SS-OCT) and full-field electroretinography (ffERG) were performed. Genomic DNA was extracted from blood samples and whole genome sequencing was performed. Variants were validated with Sanger sequencing. Results Six members in this Chinese family, including three affected individuals and three controls, were recruited in this study. The ophthalmic examination of three recruited patients was consistent with fundus albipunctatus. Three variants, a novel frameshift deletion c.39delA [p.(Val14CysfsX47] and a haplotype of two rare missense variants, c.683G > A [p.(Arg228Gln)] along with c.710A > G [p.(Tyr237Cys], within the retinal dehydrogenase 5 (RDH5) gene were found to segregate with fundus albipunctatus in this family in an autosomal recessive matter. Conclusion We identified novel compound heterozygous variants in RDH5 responsible for fundus albipunctatus in a large Chinese family. The results of our study further broaden the genetic defects of RDH5 associated with fundus albipunctatus.

关键词： Fundus albipunctatus RDH5 gene Frameshift deletion Missense variants

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A novel variant in DMXL2 gene is associated with autosomal dominant non-syndromic hearing impairment (DFNA71) in a Cameroonian family

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EXPERIMENTAL BIOLOGY AND MEDICINE 2021年第13期246卷 1524-1532页

作者： Wonkam-Tingang, Edmond schrauwen, isabelle Esoh, Kevin K. Bharadwaj, Thashi Nouel-Saied, Liz M. Acharya, Anushree Nasir, Abdul Leal, Suzanne M. Wonkam, Ambroise Univ Cape Town Fac Hlth Sci Div Human Genet ZA-7925 Cape Town South Africa Columbia Univ Med Ctr Taub Inst Alzheimers Dis & Aging Brain Ctr Stat GenetSergievsky Ctr New York NY 10032 USA Columbia Univ Med Ctr Dept Neurol New York NY 10032 USA Ajou Univ Dept Mol Sci & Technol Synthet Prot Engn Lab SPEL Suwon 443749 South Korea

Approximately half of congenital hearing impairment cases are inherited, with non-syndromic hearing impairment (NSHI) being the most frequent clinical entity of genetic hearing impairment cases. A family from Cameroon with NSHI was investigated by performing exome sequencing using DNA samples obtained from three family members, followed by direct Sanger sequencing in additional family members and controls participants. We identified an autosomal dominantly inherited novel missense variant [NM_001174116.2:c.918G>T;p.(Q306H)] in DMXL2 gene (MIM:612186) that co-segregates with mild to profound non-syndromic sensorineural hearing impairment . The p.(Q306H) variant which substitutes a highly conserved glutamine residue is predicted deleterious by various bioinformatics tools and is absent from several genome databases. This variant was also neither found in 121 apparently healthy controls without a family history of hearing impairment , nor 112 sporadic NSHI cases from Cameroon. There is one previous report of a large Han Chinese NSHI family that segregates a missense variant in DMXL2. The present study provides additional evidence that DMXL2 is involved in hearing impairment etiology, and we suggest DMXL2 should be considered in diagnostic hearing impairment panels.

关键词： Non-syndromic hearing impairment autosomal dominant inheritance DMXL2 Africa

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