Top

Published in:

Open Access 01-12-2013 | Research

Whole-genome sequencing in an autism multiplex family

Authors: Lingling Shi, Xu Zhang, Ryan Golhar, Frederick G Otieno, Mingze He, Cuiping Hou, Cecilia Kim, Brendan Keating, Gholson J Lyon, Kai Wang, Hakon Hakonarson

Published in: Molecular Autism | Issue 1/2013

Abstract

Background

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental disorders that affect 1 in 88 children in the US. Previous exome sequencing studies on family trios have implicated a role for rare, de-novo mutations in the pathogenesis of autism.

Methods

To examine the utility of whole-genome sequencing to identify inherited disease candidate variants and genes, we sequenced two probands from a large pedigree, including two parents and eight children. We evaluated multiple analytical strategies to identify a prioritized list of candidate genes.

Results

By assuming a recessive model of inheritance, we identified seven candidate genes shared by the two probands. We also evaluated a different analytical strategy that does not require the assumption of disease model, and identified a list of 59 candidate variants that may increase susceptibility to autism. Manual examination of this list identified ANK3 as the most likely candidate gene. Finally, we identified 33 prioritized non-coding variants such as those near SMG6 and COQ5, based on evolutionary constraint and experimental evidence from ENCODE. Although we were unable to confirm rigorously whether any of these genes indeed contribute to the disease, our analysis provides a prioritized shortlist for further validation studies.

Conclusions

Our study represents one of the first whole-genome sequencing studies in autism leveraging a large family-based pedigree. These results provide for a discussion on the relative merits of finding de-novo mutations in sporadic cases versus finding inherited mutations in large pedigrees, in the context of neuropsychiatric and neurodevelopmental diseases.

Available only for authorised users

American Psychiatric Association, Task Force on DSM-IV: Diagnostic and statistical manual of mental disorders: DSM-IV-TR. 2000, Washington, DC: American Psychiatric Association, 4

Jon Baio E: Prevalence of autism spectrum disorders - autism and developmental disabilities monitoring network, 14 sites, United States, 2008. Centers Dis Contr Prev. 2012, 61: 1-19.

Ganz ML: The lifetime distribution of the incremental societal costs of autism. Arch Pediatr Adolesc Med. 2007, 161: 343-349. 10.1001/archpedi.161.4.343.CrossRefPubMed

Lichtenstein P, Carlstrom E, Rastam M, Gillberg C, Anckarsater H: The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am J Psychiatry. 2010, 167: 1357-1363. 10.1176/appi.ajp.2010.10020223.CrossRefPubMed

Ma D, Salyakina D, Jaworski JM, Konidari I, Whitehead PL, Andersen AN, Hoffman JD, Slifer SH, Hedges DJ, Cukier HN, Griswold AJ, McCauley JL, Beecham GW, Wright HH, Abramson RK, Martin ER, Hussman JP, Gilbert JR, Cuccaro ML, Haines JL, Pericak-Vance MA: A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Ann Hum Genet. 2009, 73: 263-273. 10.1111/j.1469-1809.2009.00523.x.PubMedCentralCrossRefPubMed

Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, Salyakina D, Imielinski M, Bradfield JP, Sleiman PM, Kim CE, Hou C, Frackelton E, Chiavacci R, Takahashi N, Sakurai T, Rappaport E, Lajonchere CM, Munson J, Estes A, Korvatska O, Piven J, Sonnenblick LI, Alvarez Retuerto AI, Herman EI, Dong H, Hutman T, Sigman M, Ozonoff S, Klin A: Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature. 2009, 459: 528-533. 10.1038/nature07999.PubMedCentralCrossRefPubMed

Weiss LA, Arking DE, Daly MJ, Chakravarti A: A genome-wide linkage and association scan reveals novel loci for autism. Nature. 2009, 461: 802-808. 10.1038/nature08490.PubMedCentralCrossRefPubMed

Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Sykes N, Pagnamenta AT, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bolte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Carson AR, Casallo G, Casey J, Chu SH, Cochrane L, Corsello C, Crawford EL, Crossett A: A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet. 2010, 19: 4072-4082. 10.1093/hmg/ddq307.PubMedCentralCrossRefPubMed

Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G, Bolshakova N, Bolte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Casey J, Conroy J, Correia C, Corsello C, Crawford EL, De Jonge M, Delorme R, Duketis E, Dugue F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Gilbert J, Gillberg C, Glessner JT, Green A: Individual common variants exert weak effects on the risk for autism spectrum disorderspi. Hum Mol Genet. 2012, 21: 4781-4792. 10.1093/hmg/dds301.PubMedCentralCrossRefPubMed

10.

Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, Imielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PM, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer KJ, Anagnostou E, Sakurai T: Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. 2009, 459: 569-573. 10.1038/nature07953.PubMedCentralCrossRefPubMed

11.

Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bolte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BH, Cochrane L, Corsello C: Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010, 466: 368-372. 10.1038/nature09146.PubMedCentralCrossRefPubMed

12.

Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimaki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam TC: Strong association of de novo copy number mutations with autism. Science. 2007, 316: 445-449. 10.1126/science.1138659.PubMedCentralCrossRefPubMed

13.

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, Bilquvar 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: Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011, 70: 863-885. 10.1016/j.neuron.2011.05.002.PubMedCentralCrossRefPubMed

14.

Metzker ML: Sequencing technologies - the next generation. Nat Rev Genet. 2010, 11: 31-46. 10.1038/nrg2626.CrossRefPubMed

15.

Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J: Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011, 12: 745-755. 10.1038/nrg3031.CrossRefPubMed

16.

Gilissen C, Hoischen A, Brunner HG, Veltman JA: Unlocking Mendelian disease using exome sequencing. Genome Biol. 2011, 12: 228-10.1186/gb-2011-12-9-228.PubMedCentralCrossRefPubMed

17.

O’Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, Karakoc E, Mackenzie AP, Ng SB, Baker C, Rieder MJ, Nickerson DA, Bernier R, Fisher SE, Shendure J, Eichler EE: Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet. 2011, 43: 585-589. 10.1038/ng.835.PubMedCentralCrossRefPubMed

18.

O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Maliq M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE: Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012, 485: 246-250. 10.1038/nature10989.PubMedCentralCrossRefPubMed

19.

Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilquvar K, Mane SM, Sestan N, Lifton RP, Gunel M, Roeder K, Geschwind DH, Devlin B, State MW: De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012, 485: 237-241. 10.1038/nature10945.PubMedCentralCrossRefPubMed

20.

Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y: Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012, 485: 242-245. 10.1038/nature11011.PubMedCentralCrossRefPubMed

21.

Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee YH, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Fulton RS, Magrini VJ, Ye K, Darnell RB: De novo gene disruptions in children on the autistic spectrum. Neuron. 2012, 74: 285-299. 10.1016/j.neuron.2012.04.009.PubMedCentralCrossRefPubMed

22.

Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, Gudjonsson SA, Sigurdsson A, Jonasdottir A, Wong WS, Sigurdsson G, Walters GB, Steinberg S, Helgason H, Thorleifsson G, Gudbjartsson DF, Helgason A, Magnusson OT, Thorsteinsdottir U, Stefansson K: Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012, 488: 471-475. 10.1038/nature11396.PubMedCentralCrossRefPubMed

23.

Talkowski ME, Rosenfeld JA, Blumenthal I, Pillalamarri V, Chiang C, Heilbut A, Ernst C, Hanscom C, Rossin E, Lindgren AM, Pereira S, Ruderfer D, Kirby A, Ripke S, Harris DJ, Lee JH, Ha K, Kim HG, Solomon BD, Gropman AL, Lucente D, Sims K, Ohsumi TK, Borowsky ML, Loranger S, Quade B, Lage K, Miles J, Wu BL, Shen Y: Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell. 2012, 149: 525-537. 10.1016/j.cell.2012.03.028.PubMedCentralCrossRefPubMed

24.

Yu TW, Chahrour MH, Coulter ME, Jiralerspong S, Okamura-Ikeda K, Ataman B, Schmitz-Abe K, Harmin DA, Adli M, Malik AN, D’Gama AM, Lim ET, Sanders SJ, Mochida GH, Partlow JN, Sunu CM, Felie JM, Rodriguez J, Nasir RH, Ware J, Joseph RM, Hill RS, Kwan BY, Al-Saffar M, Mukkades NM, Hashmi A, Balkhy S, Gascon GG, Hisama FM, LeClair E: Using whole-exome sequencing to identify inherited causes of autism. Neuron. 2013, 77: 259-273. 10.1016/j.neuron.2012.11.002.PubMedCentralCrossRefPubMed

25.

Geschwind DH, Sowinski J, Lord C, Iversen P, Shestack J, Jones P, Ducat L, Spence SJ: The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions. Am J Hum Genet. 2001, 69: 463-466. 10.1086/321292.PubMedCentralCrossRefPubMed

26.

Drmanac R, Sparks AB, Callow MJ, Halpern AL, Burns NL, Kermani BG, Carnevali P, Nazarenko I, Nilsen GB, Yeung G: Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays. Science. 2010, 327: 78-81. 10.1126/science.1181498.CrossRefPubMed

27.

Roach JC, Boysen C, Wang K, Hood L: Pairwise end sequencing: a unified approach to genomic mapping and sequencing. Genomics. 1995, 26: 345-353. 10.1016/0888-7543(95)80219-C.CrossRefPubMed

28.

Drmanac R, Sparks AB, Callow MJ, Halpern AL, Burns NL, Kermani BG, Carnevali P, Nazarenko I, Nilsen GB, Yeung G, Dahl F, Fernandez A, Staker B, Pant KP, Baccash J, Borcherding AP, Brownley A, Cedeno R, Chen L, Chernikoff D, Cheung A, Chirita R, Curson B, Ebert JC, Hacker CR, Hartlage R, Hauser B, Huang S, Jiang Y, Karpinchyk V: Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays. Science. 2010, 327: 78-81. 10.1126/science.1181498.CrossRefPubMed

29.

Wang K, Li M, Hadley D, Liu R, Glessner J, Grant SFA, Hakonarson H, Bucan M: PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res. 2007, 17: 1665-1674. 10.1101/gr.6861907.PubMedCentralCrossRefPubMed

30.

Diskin SJ, Li M, Hou C, Yang S, Glessner J, Hakonarson H, Bucan M, Maris JM, Wang K: Adjustment of genomic waves in signal intensities from whole-genome SNP genotyping platforms. Nucleic Acids Res. 2008, 36: e126-10.1093/nar/gkn556.PubMedCentralCrossRefPubMed

31.

Zhu M, Need AC, Han Y, Ge D, Maia JM, Zhu Q, Heinzen EL, Cirulli ET, Pelak K, He M, Ruzzo EK, Gumbs C, Singh A, Feng S, Shianna KV, Goldstein DB: Using ERDS to infer copy-number variants in high-coverage genomes. Am J Hum Genet. 2012, 91: 408-421. 10.1016/j.ajhg.2012.07.004.PubMedCentralCrossRefPubMed

32.

Wang K, Li M, Hakonarson H: ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010, 38: e164-10.1093/nar/gkq603.PubMedCentralCrossRefPubMed

33.

Chang X, Wang K: wANNOVAR: annotating genetic variants for personal genomes via the web. J Med Genet. 2012, 49: 433-436. 10.1136/jmedgenet-2012-100918.PubMedCentralCrossRefPubMed

34.

Davydov EV, Goode DL, Sirota M, Cooper GM, Sidow A, Batzoglou S: Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol. 2010, 6: e1001025-10.1371/journal.pcbi.1001025.PubMedCentralCrossRefPubMed

35.

Ernst J, Kheradpour P, Mikkelsen TS, Shoresh N, Ward LD, Epstein CB, Zhang X, Wang L, Issner R, Coyne M, Ku M, Durham T, Kellis M, Bernstein BE: Mapping and analysis of chromatin state dynamics in nine human cell types. Nature. 2011, 473: 43-49. 10.1038/nature09906.PubMedCentralCrossRefPubMed

36.

Abecasis GR, Cherny SS, Cookson WO, Cardon LR: Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet. 2002, 30: 97-101. 10.1038/ng786.CrossRefPubMed

37.

Suetsugu S, Miki H, Takenawa T: Identification of two human WAVE/SCAR homologues as general actin regulatory molecules which associate with the Arp2/3 complex. Biochem Biophys Res Commun. 1999, 260: 296-302. 10.1006/bbrc.1999.0894.CrossRefPubMed

38.

Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, Zhang J, Soden R, Hayakawa M, Kreiman G, Cooke MP, Walker JR, Hogenesch JB: A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acac Sci U S A. 2004, 101: 6062-6067. 10.1073/pnas.0400782101.CrossRef

39.

Kraus DM, Elliott GS, Chute H, Horan T, Pfenninger KH, Sanford SD, Foster S, Scully S, Welcher AA, Holers VM: CSMD1 is a novel multiple domain complement-regulatory protein highly expressed in the central nervous system and epithelial tissues. J Immunol. 2006, 176: 4419-4430.CrossRefPubMed

40.

Lam HY, Clark MJ, Chen R, Natsoulis G, O’Huallachain M, Dewey FE, Habegger L, Ashley EA, Gerstein MB, Butte AJ, Ji HP, Snyder M: Performance comparison of whole-genome sequencing platforms. Nat Biotechnol. 2012, 30: 78-82.PubMedCentralCrossRef

41.

Roach JC, Glusman G, Smit AF, Huff CD, Hubley R, Shannon PT, Rowen L, Pant KP, Goodman N, Bamshad M, Shendure J, Drmanac R, Jorde LB, Hood L, Galas DJ: Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science. 2010, 328: 636-639. 10.1126/science.1186802.PubMedCentralCrossRefPubMed

42.

Lyon GJ, Jiang T, Van Wijk R, Wang W, Bodily PM, Xing J, Tian L, Robison RJ, Clement M, Lin Y, Zhang P, Liu Y, Moore B, Glessner JT, Elia J, Reimherr F, van Solinge WW, Yandell M, Hakonarson H, Wang J, Johnson WE, Wei Z, Wang K: Exome sequencing and unrelated findings in the context of complex disease research: ethical and clinical implications. Discov Med. 2011, 12: 41-55.PubMedCentralPubMed

43.

Gan SQ, McBride OW, Idler WW, Markova N, Steinert PM: Organization, structure, and polymorphisms of the human profilaggrin gene. Biochemistry. 1990, 29: 9432-9440. 10.1021/bi00492a018.CrossRefPubMed

44.

Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, Liao H, Evans AT, Goudie DR, Lewis-Jones S, Arseculeratne G, Munro CS, Sergeant A, O’Regan G, Bale SJ, Compton JG, DiGiovanna JJ, Presland RB, Fleckman P, McLean WH: Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006, 38: 337-342. 10.1038/ng1743.CrossRefPubMed

45.

Sandilands A, Terron-Kwiatkowski A, Hull PR, O’Regan GM, Clayton TH, Watson RM, Carrick T, Evans AT, Liao H, Zhao Y, Campbell LE, Schmuth M, Gruber R, Janecke R, Elias PM, van Steensel MA, Nagtzaam I, van Geel M, Steijlen PM, Munro CS, Bradley DG, Palmer CN, Smith FJ, McLean WH, Irvine AD: Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet. 2007, 39: 650-654. 10.1038/ng2020.CrossRefPubMed

46.

Steinert PM, Parry DA, Marekov LN: Trichohyalin mechanically strengthens the hair follicle: multiple cross-bridging roles in the inner root shealth. J Biol Chem. 2003, 278: 41409-41419. 10.1074/jbc.M302037200.CrossRefPubMed

47.

McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB: NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 2006, 79: 169-173. 10.1086/505332.PubMedCentralCrossRefPubMed

48.

Simpson MA, Irving MD, Asilmaz E, Gray MJ, Dafou D, Elmslie FV, Mansour S, Holder SE, Brain CE, Burton BK, Kim KH, Pauli RM, Aftimos S, Stewart H, Kim CA, Holder-Espinasse M, Robertson SP, Drake WM, Trembath RC: Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat Genet. 2011, 43: 303-305. 10.1038/ng.779.CrossRefPubMed

49.

Isidor B, Lindenbaum P, Pichon O, Bezieau S, Dina C, Jacquemont S, Martin-Coignard D, Thauvin-Robinet C, Le Merrer M, Mandel JL, David A, Faivre L, Cornier-Daire V, Redon R, Le Ciagnec C: Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet. 2011, 43: 306-308. 10.1038/ng.778.CrossRefPubMed

50.

Eschrich D, Buchhaupt M, Kotter P, Entian KD: Nep1p (Emg1p), a novel protein conserved in eukaryotes and archaea, is involved in ribosome biogenesis. Curr Genet. 2002, 40: 326-338. 10.1007/s00294-001-0269-4.CrossRefPubMed

51.

Lamont RE, Loredo-Osti J, Roslin NM, Mauthe J, Coghlan G, Nylen E, Frappier D, Innes AM, Lemire EG, Lowry RB, Greenberg CR, Triggs-Raine BL, Morgan K, Wrogemann K, Fujiwara TM, Zelinski T: A locus for Bowen-Conradi syndrome maps to chromosome region 12p13.3. Am J Med Genet A. 2005, 132A: 136-143. 10.1002/ajmg.a.30420.CrossRefPubMed

52.

Flory MR, Moser MJ, Monnat RJ, Davis TN: Identification of a human centrosomal calmodulin-binding protein that shares homology with pericentrin. Proc Natl Acac Sci U S A. 2000, 97: 5919-5923. 10.1073/pnas.97.11.5919.CrossRef

53.

Rauch A, Thiel CT, Schindler D, Wick U, Crow YJ, Ekici AB, van Essen AJ, Goecke TO, Al-Gazali L, Chrzanowska KH, Zweier C, Brunner HG, Becker K, Curry CJ, Dallapiccola B, Devriendt K, Dorfler A, Kinning E, Megarbane A, Meinecke P, Semple RK, Spranger S, Toutain A, Trembath RC, Voss E, Wilson L, Hennekam R, de Zegher F, Dorr HG, Reis A: Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science. 2008, 319: 816-819. 10.1126/science.1151174.CrossRefPubMed

54.

Henry J, Hsu CY, Haftek M, Nachat R, de Koning HD, Gardinal-Galera I, Hitomi K, Balica S, Jean-Decoster C, Schmitt AM, Paul C, Serre G, Simon M: Hornerin is a component of the epidermal cornified cell envelopes. FASEB J. 2011, 25: 1567-1576. 10.1096/fj.10-168658.CrossRefPubMed

55.

Esparza-Gordillo J, Weidinger S, Folster-Holst R, Bauerfeind A, Ruschendorf F, Patone G, Rohde K, Marenholz I, Schulz F, Kerscher T, Hubner N, Wahn U, Schreiber S, Franke A, Vogler R, Heath S, Baurecht H, Novak N, Rodriguez E, Illiq T, Lee-Kirsch MA, Ciechanowicz A, Kurek M, Piskackova T, Macek M, Lee YA, Ruether A: A common variant on chromosome 11q13 is associated with atopic dermatitis. Nat Genet. 2009, 41: 596-601. 10.1038/ng.347.CrossRefPubMed

56.

Lim ET, Raychaudhuri S, Sanders SJ, Stevens C, Sabo A, Macarthur DG, Neale BM, Kirby A, Ruderfer DM, Fromer M, Lek M, Liu L, Flannick J, Ripke S, Nagaswamy U, Muzny D, Reid JG, Hawes A, Newsham I, Wu Y, Lewis L, Dinh H, Gross S, Wang LS, Lin CF, Valladares O, Gabriel SB, dePristo M, Altshuler DM, Purcell SM: Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders. Neuron. 2013, 77: 235-242. 10.1016/j.neuron.2012.12.029.PubMedCentralCrossRefPubMed

57.

Yang J, Visscher PM, Wray NR: Sporadic cases are the norm for complex disease. Eur J Hum Genet. 2010, 18: 1039-1043. 10.1038/ejhg.2009.177.PubMedCentralCrossRefPubMed

58.

Lee SH, DeCandia TR, Ripke S, Yang J, Sullivan PF, Goddard ME, Keller MC, Visscher PM, Wray NR: Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat Genet. 2012, 44: 247-250. 10.1038/ng.1108.PubMedCentralCrossRefPubMed

59.

Kumar P, Henikoff S, Ng PC: Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009, 4: 1073-1081. 10.1038/nprot.2009.86.CrossRefPubMed

60.

Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR: A method and server for predicting damaging missense mutations. Nat Methods. 2010, 7: 248-249. 10.1038/nmeth0410-248.PubMedCentralCrossRefPubMed

61.

Siepel A, Pollard K, Haussler D: New methods for detecting lineage-specific selection. Proceedings of the 10th International Conference on Research in Computational Molecular Biology (RECOMB 2006). 2006, Berlin, heidelberg: Springer-Verlag, 190-205.

62.

da Huang W, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009, 4: 44-57.CrossRefPubMed

63.

Ferreira MA, O’Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, Fan J, Kirov G, Perlis RH, Green EK, Smoller JW, Grozeva D, Stone J, Nikolov I, Chambert K, Hamshere ML, Nimgaonkar VL, Moskvina V, Thase ME, Caesar S, Sachs GS, Franklin J, Gordon-Smith K, Ardlie KG, Gabriel SB, Fraser C, Blumenstiel B, Defelice M, Breen G, Gill M: Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet. 2008, 40: 1056-1058. 10.1038/ng.209.PubMedCentralCrossRefPubMed

64.

Schulze TG, Detera-Wadleigh SD, Akula N, Gupta A, Kassem L, Steele J, Pearl J, Strohmaier J, Breuer R, Schwarz M, Propping P, Nothen NM, Cichon S, Schumacher J, NIMH Genetics Initiative Bipolar Disorder Consortium, Rietschel M, McMahon FJ: Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder. Mol Psychiatry. 2009, 14: 487-491. 10.1038/mp.2008.134.PubMedCentralCrossRefPubMed

65.

Bi C, Wu J, Jiang T, Liu Q, Cai W, Yu P, Cai T, Zhao M, Jiang YH, Sun ZS: Mutations of ANK3 identified by exome sequencing are associated with Autism susceptibility. Hum Mutat. 2012, 33: 1635-1638. 10.1002/humu.22174.CrossRefPubMed

66.

Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, Epstein CB, Frietze S, Harrow J, Kaul R, Khatun J, Lajoie BR, Landt SG, Lee BK, Pauli F, Rosenbloom KR, Sabo P, Safi A, Sanyal A, Shoresh N, Simon JM, Song L, Trinklein ND, Altschuler RC, Birney E, Brown JB, Cheng C, Djebali S, Dong X, ENCODE Project Consortium: An integrated encyclopedia of DNA elements in the human genome. Nature. 2012, 489: 57-74. 10.1038/nature11247.CrossRef

67.

Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A, Meissner A, Kellis M, Marra MA, Beaudet AL, Ecker JR, Farnham PJ, Hirst M, Lander ES, Mikkelsen TS, Thomson JA: The NIH roadmap epigenomics mapping consortium. Nat Biotechnol. 2010, 28: 1045-1048. 10.1038/nbt1010-1045.PubMedCentralCrossRefPubMed

68.

Ward LD, Kellis M: Interpreting noncoding genetic variation in complex traits and human disease. Nat Biotechnol. 2012, 30: 1095-1106. 10.1038/nbt.2422.PubMedCentralCrossRefPubMed

69.

Barkovich RJ, Shtanko A, Shepherd JA, Lee PT, Myles DC, Tzagoloff A, Clarke CF: Characterization of the COQ5 gene from Saccharomyces cerevisiae. Evidence for a C-methyltransferase in ubiquinone biosynthesis. J Biol Chem. 1997, 272: 9182-9188. 10.1074/jbc.272.14.9182.CrossRefPubMed

70.

Fukuhara N, Ebert J, Unterholzner L, Lindner D, Izaurralde E, Conti E: SMG7 is a 14-3-3-like adaptor in the nonsense-mediated mRNA decay pathway. Mol Cell. 2005, 17: 537-547. 10.1016/j.molcel.2005.01.010.CrossRefPubMed

71.

Xu B, Roos JL, Dexheimer P, Boone B, Plummer B, Levy S, Gogos JA, Karayiorgou M: Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nat Genet. 2011, 43: 864-868. 10.1038/ng.902.PubMedCentralCrossRefPubMed

72.

Girard SL, Gauthier J, Noreau A, Xiong L, Zhou S, Jouan L, Dionne-Laporte A, Spiegelman D, Henrion E, Diallo O: Increased exonic de novo mutation rate in individuals with schizophrenia. Nat Genet. 2011, 43: 860-863. 10.1038/ng.886.CrossRefPubMed

73.

Rosenfeld JA, Mason CE, Smith TM: Limitations of the human reference genome for personalized genomics. PLoS One. 2012, 7: e40294-10.1371/journal.pone.0040294.PubMedCentralCrossRefPubMed

Title: Whole-genome sequencing in an autism multiplex family
Authors: Lingling Shi
Xu Zhang
Ryan Golhar
Frederick G Otieno
Mingze He
Cuiping Hou
Cecilia Kim
Brendan Keating
Gholson J Lyon
Kai Wang
Hakon Hakonarson
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: Molecular Autism / Issue 1/2013
Electronic ISSN: 2040-2392
DOI: https://doi.org/10.1186/2040-2392-4-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Whole-genome sequencing in an autism multiplex family

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2013

Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay

Presence of autism, hyperserotonemia, and severe expressive language impairment in Williams-Beuren syndrome

Evidence for differential alternative splicing in blood of young boys with autism spectrum disorders

Test-retest reliability of the ‘Reading the Mind in the Eyes’ test: a one-year follow-up study

SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs)

Task-related functional connectivity in autism spectrum conditions: an EEG study using wavelet transform coherence