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Exome sequencing, hearing loss

Zhen Zhang, Quan-Dong Chen, Li-Ping Zhao, Jing Ma, Tie-Song Zhang, Jing-Xue Pang, Yang-Fang Li, Mei-Fen Wang, Ai-Ping Wang, Li Tang, Li-Jun Li, Wen-Ji He, Huaiyu Gu
Deafness and hearing loss may have functional, economic, social and emotional impacts on humans, including the ability of an individual to communicate with others, feelings of isolation and frustration, and health sector costs. The World Health Organization reported that there are 32 million children worldwide with hearing loss. In order to investigate genetic mutations in children of 26 nationalities with hearing loss in Yunnan, Sanger sequencing was employed to screen for mutations in four of the most common pathological genes, including gap junction protein β2 and 3, solute carrier family 26 member 4 and mitochondrial DNA...
February 22, 2018: Molecular Medicine Reports
Mun Young Chang, Chung Lee, Jin Hee Han, Min Young Kim, Hye-Rim Park, Nayoung Kim, Woong-Yang Park, Doo Yi Oh, Byung Yoon Choi
BACKGROUND: MYO15A variants, except those in the N-terminal domain, have been shown to be associated with congenital or pre-lingual severe-to-profound hearing loss (DFNB3), which ultimately requires cochlear implantation in early childhood. Recently, such variants have also been shown to possibly cause moderate-to-severe hearing loss. Herein, we also demonstrate that some MYO15A mutant alleles can cause postlingual onset of progressive partial deafness. METHODS: Two multiplex Korean families (SB246 and SB224), manifesting postlingual, progressive, partial deafness in an autosomal recessive fashion, were recruited...
February 27, 2018: BMC Medical Genetics
Xue Gao, Yong-Yi Yuan, Qiong-Fen Lin, Jin-Cao Xu, Wei-Qian Wang, Yue-Hua Qiao, Dong-Yang Kang, Dan Bai, Feng Xin, Sha-Sha Huang, Shi-Wei Qiu, Li-Ping Guan, Yu Su, Guo-Jian Wang, Ming-Yu Han, Yi Jiang, Han-Kui Liu, Pu Dai
Background Hereditary sensorineural hearing loss is a genetically heterogeneous disorder. Objectives This study was designed to explore the genetic etiology of deafness in a large Chinese family with autosomal dominant, nonsyndromic, progressive sensorineural hearing loss (ADNSHL). Methods Whole exome sequencing and linkage analysis were performed to identify pathogenic mutation. Inner ear expression of Ifnlr1 was investigated by immunostaining in mice. ifnlr1 Morpholino knockdown Zebrafish were constructed to explore the deafness mechanism...
February 16, 2018: Journal of Medical Genetics
Hongbo Cheng, Qin Zhang, Wenbin Wang, Qingxia Meng, Fuxin Wang, Minjuan Liu, Jun Mao, Yichao Shi, Wei Wang, Hong Li
OBJECTIVES: To identify the pathogenic mutation and provide prenatal counseling and diagnosis in two large Chinese families with autosomal dominant all-frequency hearing loss. METHODS: Whole exome sequencing technology was used to identify the pathogenic mutation of the two families. In addition, 298 patients with sporadic hearing loss and 400 normal controls were studied to verify the mutation/polymorphism nature of the identified variant. Prenatal diagnosis was carried out...
March 2018: International Journal of Pediatric Otorhinolaryngology
Clothilde Esteve, Ludmila Francescatto, Perciliz L Tan, Aurélie Bourchany, Cécile De Leusse, Evelyne Marinier, Arnaud Blanchard, Patrice Bourgeois, Céline Brochier-Armanet, Ange-Line Bruel, Arnauld Delarue, Yannis Duffourd, Emmanuelle Ecochard-Dugelay, Géraldine Hery, Frédéric Huet, Philippe Gauchez, Emmanuel Gonzales, Catherine Guettier-Bouttier, Mina Komuta, Caroline Lacoste, Raphaelle Maudinas, Karin Mazodier, Yves Rimet, Jean-Baptiste Rivière, Bertrand Roquelaure, Sabine Sigaudy, Xavier Stephenne, Christel Thauvin-Robinet, Julien Thevenon, Jacques Sarles, Nicolas Levy, Catherine Badens, Olivier Goulet, Jean-Pierre Hugot, Nicholas Katsanis, Laurence Faivre, Alexandre Fabre
Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function...
February 1, 2018: American Journal of Human Genetics
Luitgard M Graul-Neumann, Martin A Mensah, Eva Klopocki, Steffen Uebe, Arif B Ekici, Christian T Thiel, André Reis, Christiane Zweier
3MC syndrome is a rare autosomal recessive disorder with characteristic craniofacial dysmorphism and multiple anomalies. It is caused by biallelic mutations in one of three genes, MASP1, COLEC11 and COLEC10, all encoding factors of the lectin complement pathway. In MASP1, either truncating mutations or missense variants in exon 12 encoding the C-terminal serine protease domain specific for isoform MASP-3 are causative. By trio exome sequencing we now identified a novel, homozygous 2kb deletion, partially affecting exon 12 in an adult female with the typical facial gestalt of 3MC syndrome and hearing loss, but without the main feature cleft lip/palate, and without intellectual disability, or short stature...
January 30, 2018: European Journal of Medical Genetics
Sanna Puusepp, Reka Kovacs-Nagy, Bader Alhaddad, Matthias Braunisch, Georg F Hoffmann, Urania Kotzaeridou, Lucia Lichvarova, Mailis Liiv, Christine Makowski, Merle Mandel, Thomas Meitinger, Sander Pajusalu, Richard J Rodenburg, Dzhamilja Safiulina, Tim M Strom, Inga Talvik, Annika Vaarmann, Callum Wilson, Allen Kaasik, Tobias B Haack, Katrin Õunap
Variants in the SPATA5 gene were recently described in a cohort of patients with global developmental delay, sensorineural hearing loss, seizures, cortical visual impairment and microcephaly. SPATA5 protein localizes predominantly in the mitochondria and is proposed to be involved in mitochondrial function and brain developmental processes. However no functional studies have been performed. This study describes five patients with psychomotor developmental delay, microcephaly, epilepsy and hearing impairment, who were thought clinically to have a mitochondrial disease with subsequent whole-exome sequencing analysis detecting compound heterozygous variants in the SPATA5 gene...
January 17, 2018: European Journal of Human Genetics: EJHG
Yan Sun, Xuyun Hu, Jiqing Song, Yanyan Hu, Caihong Liu, Guimei Li
INTRODUCTION: RNASET2 mutation has been reported in patients with cystic leukoencephalopathy without megalencephaly and the Aicardi-Goutieres syndrome. Both disorders are Mendelian mimics of congenital cytomegalovirus infection with overlapping features, including leukoencephalopathy, white matter alterations, intracranial calcification, delayed psychomotor development, intelligence disability and seizures. Only eight families with RNASET2 mutation have been previously reported. METHODS: Whole exome sequencing was performed and copy number variants were described by read-depth strategy...
January 16, 2018: Fetal and Pediatric Pathology
Amanda Moccia, Anshika Srivastava, Jennifer M Skidmore, John A Bernat, Marsha Wheeler, Jessica X Chong, Deborah Nickerson, Michael Bamshad, Margaret A Hefner, Donna M Martin, Stephanie L Bielas
PurposeCHARGE syndrome is an autosomal-dominant, multiple congenital anomaly condition characterized by vision and hearing loss, congenital heart disease, and malformations of craniofacial and other structures. Pathogenic variants in CHD7, encoding adenosine triphosphate-dependent chromodomain helicase DNA binding protein 7, are present in the majority of affected individuals. However, no causal variant can be found in 5-30% (depending on the cohort) of individuals with a clinical diagnosis of CHARGE syndrome...
January 4, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Samer Khateb, Björn Kowalewski, Nicola Bedoni, Markus Damme, Netta Pollack, Ann Saada, Alexey Obolensky, Tamar Ben-Yosef, Menachem Gross, Thomas Dierks, Eyal Banin, Carlo Rivolta, Dror Sharon
PurposeWe aimed to identify the cause of disease in patients suffering from a distinctive, atypical form of Usher syndrome.MethodsWhole-exome and genome sequencing were performed in five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and sensorineural hearing loss. Functional analysis of the wild-type and mutant proteins was performed in human fibrosarcoma cells.ResultsWe identified a homozygous founder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG)...
January 4, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Zhijie Niu, Denise Yan, Sara Bressler, Lingyun Mei, Yong Feng, Xuezhong Liu
OBJECTIVE: X-linked nonsyndromic hearing impairment is the rarest form of genetic hearing loss and represents only a minor fraction of all cases. The aim of this study was to investigate the cause of X-linked nonsyndromic sensorineural hearing loss in a three-generation American family. METHODS: Whole-exome sequencing and co-segregation analysis were used to identify disease-causing genes. RESULTS: In this study, we described in detail the clinical characteristics of the family and identified a novel frameshift mutation creating a premature stop codon (c...
January 2018: International Journal of Pediatric Otorhinolaryngology
Mojgan Babanejad, Omid Ali Adeli, Nooshin Nikzat, Maryam Beheshtian, Hakimeh Azarafra, Farnaz Sadeghnia, Marzieh Mohseni, Hossein Najmabadi, Kimia Kahrizi
INTRODUCTION: Autosomal recessive cerebellar ataxias (ARCAs) are a large group of neurodegenerative disorders that manifest mainly in children and young adults. Most ARCAs are heterogeneous with respect to age at onset, severity of disease progression, and frequency of extracerebellar and systemic signs. METHODS: The phenotype of a consanguineous Iranian family was characterized using clinical testing and pedigree analysis. Whole-exome sequencing was used to identify the disease-causing gene in this family...
January 2018: International Journal of Pediatric Otorhinolaryngology
A Kemal Topaloğlu
Traditionally, idiopathic hypogonadotropic hypogonadism (IHH) is divided into two major categories: Kallmann syndrome (KS) and normosmic IHH (nIHH). To date, inactivating variants in more than 50 genes have been reported to cause IHH. These mutations are estimated to account for up to 50% of all apparently hereditary cases. Identification of further causative gene mutations is expected to be more feasible with the increasing use of whole exome/genome sequencing. Presence of more than one IHH-associated mutant gene in a given patient/pedigree (oligogenic inheritance) is seen in 10-20% of all IHH cases...
December 30, 2017: Journal of Clinical Research in Pediatric Endocrinology
Hye Ji Choi, Joon Suk Lee, Seyoung Yu, Do Hyeon Cha, Heon Yung Gee, Jae Young Choi, Jong Dae Lee, Jinsei Jung
BACKGROUND: Low-frequency nonsyndromic hearing loss (LF-NSHL) is a rare, inherited disorder. Here, we report a family with LF-NSHL in whom a missense mutation was found in the Wolfram syndrome 1 (WFS1) gene. CASE PRESENTATION: Family members underwent audiological and imaging evaluations, including pure tone audiometry and temporal bone computed tomography. Blood samples were collected from two affected and two unaffected subjects. To determine the genetic background of hearing loss in this family, genetic analysis was performed using whole-exome sequencing...
December 19, 2017: BMC Medical Genetics
Romain Luscan, Sabrina Mechaussier, Antoine Paul, Guoling Tian, Xavier Gérard, Sabine Defoort-Dellhemmes, Natalie Loundon, Isabelle Audo, Sophie Bonnin, Jean-François LeGargasson, Julien Dumont, Nicolas Goudin, Meriem Garfa-Traoré, Marc Bras, Aurore Pouliet, Bettina Bessières, Nathalie Boddaert, José-Alain Sahel, Stanislas Lyonnet, Josseline Kaplan, Nicholas J Cowan, Jean-Michel Rozet, Sandrine Marlin, Isabelle Perrault
Leber congenital amaurosis (LCA) is a neurodegenerative disease of photoreceptor cells that causes blindness within the first year of life. It occasionally occurs in syndromic metabolic diseases and plurisystemic ciliopathies. Using exome sequencing in a multiplex family and three simplex case subjects with an atypical association of LCA with early-onset hearing loss, we identified two heterozygous mutations affecting Arg391 in β-tubulin 4B isotype-encoding (TUBB4B). Inspection of the atomic structure of the microtubule (MT) protofilament reveals that the β-tubulin Arg391 residue contributes to a binding pocket that interacts with α-tubulin contained in the longitudinally adjacent αβ-heterodimer, consistent with a role in maintaining MT stability...
December 7, 2017: American Journal of Human Genetics
Moumita Barua, Rohan John, Lorenzo Stella, Weili Li, Nicole M Roslin, Bedra Sharif, Saidah Hack, Ginette Lajoie-Starkell, Andrew L Schwaderer, Brian Becknell, Matthias Wuttke, Anna Köttgen, Daniel Cattran, Andrew D Paterson, York Pei
Alport syndrome is a rare hereditary disorder caused by rare variants in 1 of 3 genes encoding for type IV collagen. Rare variants in COL4A5 on chromosome Xq22 cause X-linked Alport syndrome, which accounts for ∼80% of the cases. Alport syndrome has a variable clinical presentation, including progressive kidney failure, hearing loss, and ocular defects. Exome sequencing performed in 2 affected related males with an undefined X-linked glomerulopathy characterized by global and segmental glomerulosclerosis, mesangial hypercellularity, and vague basement membrane immune complex deposition revealed a COL4A5 sequence variant, a substitution of a thymine by a guanine at nucleotide 665 (c...
March 2018: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
Agnieszka Pollak, Urszula Lechowicz, Victor Abel Murcia Pieńkowski, Piotr Stawiński, Joanna Kosińska, Henryk Skarżyński, Monika Ołdak, Rafał Płoski
BACKGROUND: Implementation of whole exome sequencing has provided unique opportunity for a wide screening of causative variants in genetically heterogeneous diseases, including nonsyndromic hearing impairment. TRIOBP in the inner ear is responsible for proper structure and function of stereocilia and is necessary for sound transduction. METHODS: Whole exome sequencing followed by Sanger sequencing was conducted on patients derived from Polish hearing loss family...
December 2, 2017: BMC Medical Genetics
Graeme A M Nimmo, Resham Ejaz, Dawn Cordeiro, Peter Kannu, Saadet Mercimek-Andrews
Biallelic likely pathogenic variants in SLC52A2 and SLC52A3 cause riboflavin transporter deficiency. It is characterized by muscle weakness, ataxia, progressive ponto-bulbar palsy, amyotrophy, and sensorineural hearing loss. Oral riboflavin halts disease progression and may reverse symptoms. We report two new patients whose clinical and biochemical features were mimicking mitochondrial myopathy. Patient 1 is an 8-year-old male with global developmental delay, axial and appendicular hypotonia, ataxia, and sensorineural hearing loss...
February 2018: American Journal of Medical Genetics. Part A
Kyu-Hee Han, Doo-Yi Oh, Seungmin Lee, Chung Lee, Jin Hee Han, Min Young Kim, Hye-Rim Park, Moo Kyun Park, Nayoung K D Kim, Jaekwang Lee, Eunyoung Yi, Jong-Min Kim, Jeong-Whun Kim, Jong-Hee Chae, Seung Ha Oh, Woong-Yang Park, Byung Yoon Choi
The etiologies and prevalence of sporadic, postlingual-onset, progressive auditory neuropathy spectrum disorder (ANSD) have rarely been documented. Thus, we aimed to evaluate the prevalence and molecular etiologies of these cases. Three out of 106 sporadic progressive hearing losses turned out to manifest ANSD. Through whole exome sequencing and subsequent bioinformatics analysis, two out of the three were found to share a de novo variant, p.E818K of ATP1A3, which had been reported to cause exclusively CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome...
November 28, 2017: Scientific Reports
Peter J Kullar, Aurora Gomez-Duran, Payam A Gammage, Caterina Garone, Michal Minczuk, Zoe Golder, Janet Wilson, Julio Montoya, Sanna Häkli, Mikko Kärppä, Rita Horvath, Kari Majamaa, Patrick F Chinnery
The m.1555A>G mtDNA variant causes maternally inherited deafness, but the reasons for the highly variable clinical penetrance are not known. Exome sequencing identified a heterozygous start loss mutation in SSBP1, encoding the single stranded binding protein 1 (SSBP1), segregating with hearing loss in a multi-generational family transmitting m.1555A>G, associated with mtDNA depletion and multiple deletions in skeletal muscle. The SSBP1 mutation reduced steady state SSBP1 levels leading to a perturbation of mtDNA metabolism, likely compounding the intra-mitochondrial translation defect due to m...
January 1, 2018: Brain: a Journal of Neurology
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