Exome sequencing and genome-wide copy number variant mapping reveal novel associations with sensorineural hereditary hearing loss

BMC Genomics

Michael P Snyder⁶  Iris Schrijver⁵  John S Oghalai¹  Kari C Nadeau⁵  Joel Gelernter³  Juan Rodriguez-Paris²  Fereshteh Jahanbani⁶  Rajini R Haraksingh⁴ 

[1] Department of Otolaryngology – Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA;Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA;Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA;Stanford University School of Medicine, 3165 Porter Drive - Room 2270, Palo Alto, CA 94304, USA;Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA;Department of Genetics, Stanford University School of Medicine, 300 Pasteur Dr., M-344A, Stanford, CA 94305, USA

关键词: Array Comparative Genome Hybridization (aCGH);    Copy number variation;    Exome sequencing;    MYH7B;    Hereditary Hearing Loss;   

Others  :  1122587
DOI  :  10.1186/1471-2164-15-1155

 received in 2014-03-20, accepted in 2014-12-12,  发布年份 2014

【 摘 要 】

Background

The genetic diversity of loci and mutations underlying hereditary hearing loss is an active area of investigation. To identify loci associated with predominantly non-syndromic sensorineural hearing loss, we performed exome sequencing of families and of single probands, as well as copy number variation (CNV) mapping in a case–control cohort.

Results

Analysis of three distinct families revealed several candidate loci in two families and a single strong candidate gene, MYH7B, for hearing loss in one family. MYH7B encodes a Type II myosin, consistent with a role for cytoskeletal proteins in hearing. High-resolution genome-wide CNV analysis of 150 cases and 157 controls revealed deletions in genes known to be involved in hearing (e.g. GJB6, OTOA, and STRC, encoding connexin 30, otoancorin, and stereocilin, respectively), supporting CNV contributions to hearing loss phenotypes. Additionally, a novel region on chromosome 16 containing part of the PDXDC1 gene was found to be frequently deleted in hearing loss patients (OR = 3.91, 95% CI: 1.62-9.40, p = 1.45 × 10^-7).

Conclusions

We conclude that many known as well as novel loci and distinct types of mutations not typically tested in clinical settings can contribute to the etiology of hearing loss. Our study also demonstrates the challenges of exome sequencing and genome-wide CNV mapping for direct clinical application, and illustrates the need for functional and clinical follow-up as well as curated open-access databases.

【 授权许可】

   
2014 Haraksingh et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Hilgert N, Smith RJ, Van Camp G: Forty-Six Genes Causing Nonsyndromic Hearing Impairment: Which Ones Should Be Analyzed in Dna Diagnostics? Mutat Res 2009, 681(2-3):189-196.
• [2]Petit C, Levilliers J, Hardelin JP: Molecular Genetics of Hearing Loss. Annu Rev Genet 2001, 35:589-646.
• [3]Morton CC, Nance WE: Newborn Hearing Screening--a Silent Revolution. N Engl J Med 2006, 354(20):2151-2164.
• [4]Dror AA, Avraham KB: Hearing Loss: Mechanisms Revealed by Genetics and Cell Biology. Annu Rev Genet 2009, 43:411-137.
• [5]Girotto G, Pirastu N, Sorice R, Biino G, Campbell H, D'Adamo AP, Hastie ND, Nutile T, Polasek O, Portas L, Rudan I, Ulivi S, Zemunik T, Wright AF, Ciullo M, Hayward C, Pirastu M, Gasparini P: Hearing Function and Thresholds: A Genome-Wide Association Study in European Isolated Populations Identifies New Loci and Pathways. J Med Genet 2011, 48(6):369-74.
• [6]Francey LJ, Conlin LK, Kadesch HE, Clark D, Berrodin D, Sun Y, Glessner J, Hakonarson H, Jalas C, Landau C, Spinner NB, Kenna M, Sagi M, Rehm HL, Krantz ID: Genome-Wide Snp Genotyping Identifies the Stereocilin (Strc) Gene as a Major Contributor to Pediatric Bilateral Sensorineural Hearing Impairment. Am J Med Genet A 2012, 158A(2):298-308.
• [7]Mills RE, Walter K, Stewart C, Handsaker RE, Chen K, Alkan C, Abyzov A, Yoon SC, Ye K, Cheetham RK, Chinwalla A, Conrad DF, Fu Y, Grubert F, Hajirasouliha I, Hormozdiari F, Iakoucheva LM, Iqbal Z, Kang S, Kidd JM, Konkel MK, Korn J, Khurana E, Kural D, Lam HY, Leng J, Li R, Li Y, Lin CY, Luo R, Mu XJ, Nemesh J, Peckham HE, Rausch T, Scally A, Shi XM, Stromberg P, Stütz AM, Urban AE, Walker JA, Wu J, Zhang Y, Zhang ZD, Batzer MA, Ding L, Marth GT, McVean G, Sebat J, Snyder M, Wang J, Eichler EE, Gerstein MB, Hurles ME, Lee C, McCarroll SA, Korbel JO, 1000 Genomes Project: Mapping Copy Number Variation by Population-Scale Genome Sequencing. Nature 2011, 470(7332):59-65.
• [8]Hasin Y, Olender T, Khen M, Gonzaga-Jauregui C, Kim PM, Urban AE, Snyder M, Gerstein MB, Lancet D, Korbel JO: High-Resolution Copy-Number Variation Map Reflects Human Olfactory Receptor Diversity and Evolution. PLoS Genet 2008, 4(11):e1000249.
• [9]Park G, Gim J, Kim A, Han KH, Kim HS, Oh SH, Park T, Park WY, Choi B: Multiphasic Analysis of Whole Exome Sequencing Data Identifies a Novel Mutation of Actg1 in a Nonsyndromic Hearing Loss Family. BMC Genomics 2013, 14:191. BioMed Central Full Text
• [10]Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME, McVean GA, 1000 Genomes Project Consortium: A Map of Human Genome Variation from Population-Scale Sequencing. Nature 2010, 467(7319):1061-1073.
• [11]Lam HY, Pan C, Clark MJ, Lacroute P, Chen R, Haraksingh R, O'Huallachain M, Gerstein MB, Kidd JM, Bustamante CD, Snyder M: Detecting and Annotating Genetic Variations Using the Hugeseq Pipeline. Nat Biotechnol 2012, 30(3):226-229.
• [12]Clark MJ, Chen R, Lam HY, Karczewski KJ, Euskirchen G, Butte AJ, Snyder M: Performance Comparison of Exome Dna Sequencing Technologies. Nat Biotechnol 2011, 29(10):908-914.
• [13]Haraksingh RR, Abyzov A, Gerstein M, Urban AE, Snyder M: Genome-Wide Mapping of Copy Number Variation in Humans: Comparative Analysis of High Resolution Array Platforms. PLoS One 2011, 6:e27859.
• [14]Conrad DF, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y, Aerts J, Andrews TD, Barnes C, Campbell P, Fitzgerald T, Hu M, Ihm CH, Kristiansson K, Macarthur DG, Macdonald JR, Onyiah I, Pang AW, Robson S, Stirrups K, Valsesia A, Walter K, Wei J, Tyler-Smith C, Carter NP, Lee C, Scherer SW, Hurles ME, Wellcome Trust Case Control Consortium: Origins and Functional Impact of Copy Number Variation in the Human Genome. Nature 2010, 464(7289):704-712.
• [15]Walsh T, Shahin H, Elkan-Miller T, Lee MK, Thornton AM, Roeb W, Abu Rayyan A, Loulus S, Avraham KB, King MC, Kanaan M: Whole Exome Sequencing and Homozygosity Mapping Identify Mutation in the Cell Polarity Protein Gpsm2 as the Cause of Nonsyndromic Hearing Loss Dfnb82. Am J Hum Genet 2010, 87(1):90-94.
• [16]Diaz-Horta O, Duman D, Foster J, Sırmacı A, Gonzalez M, Mahdieh N, Fotouhi N, Bonyadi M, Cengiz FB, Menendez I, Ulloa RH, Edwards YJ, Züchner S, Blanton S, Tekin M: Whole-Exome Sequencing Efficiently Detects Rare Mutations in Autosomal Recessive Nonsyndromic Hearing Loss. PLoS One 2012, 7(11):e50628.
• [17]Gao J, Xue J, Chen L, Ke X, Qi Y, Liu Y: Whole Exome Sequencing Identifies a Novel Dfna9 Mutation, C162y. Clin Genet 2013, 83(5):477-81.
• [18]Sirmaci A, Edwards YJ, Akay H, Tekin M: Challenges in Whole Exome Sequencing: An Example from Hereditary Deafness. PLoS One 2012, 7(2):e32000.
• [19]Woo HM, Park HJ, Baek JI, Park MH, Kim UK, Sagong B, Koo SK: Whole-Exome Sequencing Identifies Myo15a Mutations as a Cause of Autosomal Recessive Nonsyndromic Hearing Loss in Korean Families. BMC Med Genet 2013, 14:72.
• [20]Shearer AE, Black-Ziegelbein EA, Hildebrand MS, Eppsteiner RW, Ravi H, Joshi S, Guiffre AC, Sloan CM, Happe S, Howard SD, Novak B, Deluca AP, Taylor KR, Scheetz TE, Braun TA, Casavant TL, Kimberling WJ, Leproust EM, Smith RJ: Advancing Genetic Testing for Deafness with Genomic Technology. J Med Genet 2013, 50(9):627-634.
• [21]Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J: A General Framework for Estimating the Relative Pathogenicity of Human Genetic Variants. Nat Genet 2014, 46(3):310-315.
• [22]Yoon H, Lee DJ, Kim MH, Bok J: Identification of Genes Concordantly Expressed with Atoh1 During Inner Ear Development. Anat Cell Biol 2011, 44(1):69-78.
• [23]Rubio MD, Johnson R, Miller CA, Huganir RL, Rumbaugh G: Regulation of Synapse Structure and Function by Distinct Myosin Ii Motors. J Neurosci 2011, 31(4):1448-1460.
• [24]Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA, van de Lagemaat LN, Smith KA, Ebbert A, Riley ZL, Abajian C, Beckmann CF, Bernard A, Bertagnolli D, Boe AF, Cartagena PM, Chakravarty MM, Chapin M, Chong J, Dalley RA, Daly BD, Dang C, Datta S, Dee N, Dolbeare TA, Faber V, Feng D, Fowler DR, Goldy J, Gregor BW, et al.: An Anatomically Comprehensive Atlas of the Adult Human Brain Transcriptome. Nature 2012, 489(7416):391-399.
• [25]Lerer I, Sagi M, Ben-Neriah Z, Wang T, Levi H, Abeliovich D: A Deletion Mutation in Gjb6 Cooperating with a Gjb2 Mutation in Trans in Non-Syndromic Deafness: A Novel Founder Mutation in Ashkenazi Jews. Hum Mutat 2001, 18(5):460.
• [26]del Castillo I, Villamar M, Moreno-Pelayo MA, del Castillo FJ, Alvarez A, Tellería D, Menéndez I, Moreno F: A Deletion Involving the Connexin 30 Gene in Nonsyndromic Hearing Impairment. N Engl J Med 2002, 346(4):243-249.
• [27]Pallares-Ruiz N, Blanchet P, Mondain M, Claustres M, Roux AF: A Large Deletion Including Most of Gjb6 in Recessive Non Syndromic Deafness: A Digenic Effect? Eur J Hum Genet 2002, 10(1):72-76.
• [28]Del Castillo I, Moreno-Pelayo MA, Del Castillo FJ, Brownstein Z, Marlin S, Adina Q, Cockburn DJ, Pandya A, Siemering KR, Chamberlin GP, Ballana E, Wuyts W, Maciel-Guerra AT, Alvarez A, Villamar M, Shohat M, Abeliovich D, Dahl HH, Estivill X, Gasparini P, Hutchin T, Nance WE, Sartorato EL, Smith RJ, Van Camp G, Avraham KB, Petit C, Moreno F: Prevalence and Evolutionary Origins of the Del(Gjb6-D13s1830) Mutation in the Dfnb1 Locus in Hearing-Impaired Subjects: A Multicenter Study. Am J Hum Genet 2003, 73(6):1452-1458.
• [29]del Castillo FJ, Rodríguez-Ballesteros M, Alvarez A, Hutchin T, Leonardi E, de Oliveira CA, Azaiez H, Brownstein Z, Avenarius MR, Marlin S, Pandya A, Shahin H, Siemering KR, Weil D, Wuyts W, Aguirre LA, Martín Y, Moreno-Pelayo MA, Villamar M, Avraham KB, Dahl HH, Kanaan M, Nance WE, Petit C, Smith RJ, Van Camp G, Sartorato EL, Murgia A, Moreno F, del Castillo I: A Novel Deletion Involving the Connexin-30 Gene, Del(Gjb6-D13s1854), Found in Trans with Mutations in the Gjb2 Gene (Connexin-26) in Subjects with Dfnb1 Non-Syndromic Hearing Impairment. J Med Genet 2005, 42(7):588-594.
• [30]Wilch E, Zhu M, Burkhart KB, Regier M, Elfenbein JL, Fisher RA, Friderici KH: Expression of Gjb2 and Gjb6 Is Reduced in a Novel Dfnb1 Allele. Am J Hum Genet 2006, 79(1):174-179.
• [31]Feldmann D, Le Maréchal C, Jonard L, Thierry P, Czajka C, Couderc R, Ferec C, Denoyelle F, Marlin S, Fellmann F: A New Large Deletion in the Dfnb1 Locus Causes Nonsyndromic Hearing Loss. Eur J Med Genet 2009, 52:195-200.
• [32]Wilch E, Azaiez H, Fisher RA, Elfenbein J, Murgia A, Birkenhäger R, Bolz H, Da Silva-Costa SM, Del Castillo I, Haaf T, Hoefsloot L, Kremer H, Kubisch C, Le Marechal C, Pandya A, Sartorato EL, Schneider E, Van Camp G, Wuyts W, Smith RJ, Friderici KH: A Novel Dfnb1 Deletion Allele Supports the Existence of a Distant Cis-Regulatory Region That Controls Gjb2 and Gjb6 Expression. Clin Genet 2010, 78(3):267-274.
• [33]Rodriguez-Paris J, Tamayo ML, Gelvez N, Schrijver I: Allele-Specific Impairment of Gjb2 Expression by Gjb6 Deletion Del(Gjb6-D13s1854). PLoS One 2011, 6(6):e21665.
• [34]Rodriguez-Paris J, Schrijver I: The Digenic Hypothesis Unraveled: The Gjb6 Del(Gjb6-D13s1830) Mutation Causes Allele-Specific Loss of Gjb2 Expression in Cis. Biochem Biophys Res Commun 2009, 2:354-359.
• [35]Rossi AC, Mammucari C, Argentini C, Reggiani C, Schiaffino S: Two Novel/Ancient Myosins in Mammalian Skeletal Muscles: Myh14/7b and Myh15 Are Expressed in Extraocular Muscles and Muscle Spindles. J Physiol 2010, 588(2):353-364.
• [36]Diez-Roux G, Banfi S, Sultan M, Geffers L, Anand S, Rozado D, Magen A, Canidio E, Pagani M, Peluso I, Lin-Marq N, Koch M, Bilio M, Cantiello I, Verde R, De Masi C, Bianchi SA, Cicchini J, Perroud E, Mehmeti S, Dagand E, Schrinner S, Nürnberger A, Schmidt K, Metz K, Zwingmann C, Brieske N, Springer C, Hernandez AM, Herzog S, et al.: A High-Resolution Anatomical Atlas of the Transcriptome in the Mouse Embryo. PLoS Biol 2011, 9(1):e1000582.
• [37]Hainsworth DP, Bierly JR, Schmeisser ET, Baker RS: Corneal Topographic Changes after Extraocular Muscle Surgery. J AAPOS 1999, 3:80-86.
• [38]Magdaleno S, Jensen P, Brumwell CL, Seal A, Lehman K, Asbury A, Cheung T, Cornelius T, Batten DM, Eden C, Norland SM, Rice DS, Dosooye N, Shakya S, Mehta P, Curran T: Bgem: An in Situ Hybridization Database of Gene Expression in the Embryonic and Adult Mouse Nervous System. PLoS Biol 2006, 4(4):e86.
• [39]Gardner P, Oitmaa E, Messner A, Hoefsloot L, Metspalu A, Schrijver I: Simultaneous Multigene Mutation Detection in Patients with Sensorineural Hearing Loss through a Novel Diagnostic Microarray: A New Approach for Newborn Screening Follow-Up. Pediatrics 2006, 118(3):985-994.
• [40]Reumers J, De Rijk P, Zhao H, Liekens A, Smeets D, Cleary J, Van Loo P, Van Den Bossche M, Catthoor K, Sabbe B, Despierre E, Vergote I, Hilbush B, Lambrechts D, Del-Favero J: Optimized Filtering Reduces the Error Rate in Detecting Genomic Variants by Short-Read Sequencing. Nat Biotechnol 2012, 30(1):61-68.
• [41]Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PB, Choi M, Crawford EL, Davis L, Wright NR, Dhodapkar RM, DiCola M, DiLullo NM, Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS, Kammela S, Klei L, Lowe JK, Lund SC, McGrew AD, Meyer AD, Moffat WJ, Murdoch JD, O'Roak BJ, Ober GT, Pottenger RS, Raubeson MJ, Song Y, Wang Q, Yaspan BL, Yu TW, Yurkiewicz IR, Beaudet AL, Cantor RM, Curland M, Grice DE, Günel M, Lifton RP, Mane SM, Martin DM, Shaw CA, Sheldon M, Tischfield JA, Walsh CA, Morrow EM, Ledbetter DH, Fombonne E, Lord C, Martin CL, Brooks AI, Sutcliffe JS, Cook EH, Geschwind D, Roeder K, Devlin B, State MW: Multiple Recurrent De Novo Cnvs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism. Neuron 2011, 70(5):863-885.
• [42]Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC: Plink: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses. Am J Hum Genet 2007, 81(3):559-575.
• [43]Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D: Principal Components Analysis Corrects for Stratification in Genome-Wide Association Studies. Nat Genet 2006, 38(8):904-909.