Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

Journal of Medical Genetics

Volumn 51, Issue 11, 2014, Pages 724-736

  Redin, Claire ^a,b   Gérard, Bénédicte ^c   Lauer, Julia ^c   Herenger, Yvan ^c   Muller, Jean ^a,c   Quartier, Angélique ^a,b   Masurel Paulet, Alice ^d   Willems, Marjolaine ^e   Lesca, Gaétan ^f   El Chehadeh, Salima ^d   Gras, Stéphanie Le ^a   Vicaire, Serge ^a   Philipps, Muriel ^a   Dumas, Michaël ^a   Geoffroy, Véronique ^a   Feger, Claire ^a   Haumesser, Nicolas ^a,b   Alembik, Yves ^g   Barth, Magalie ^h   Bonneau, Dominique ^h   Colin, Estelle ^h   Dollfus, Hélène ^c   Doray, Bérénice ^g   Delrue, Marie Ange ⁱ   Drouin Garraud, Valérie ^j   Flori, Elisabeth ^g   Fradin, Mélanie ^k   Francannet, Christine ^l   Goldenberg, Alice ^j   Lumbroso, Serge ^m   Mathieu Dramard, Michèle ⁿ   Martin Coignard, Dominique ^o   Lacombe, Didier ⁱ   Morin, Gilles ⁿ   Polge, Anne ^m   Sukno, Sylvie ^p   Thauvin Robinet, Christel ^d   Thevenon, Julien ^d   Doco Fenzy, Martine ^q   Genevieve, David ^e   Sarda, Pierre ^e   Edery, Patrick ^f   Isidor, Bertrand ^r   Jost, Bernard ^a   Olivier Faivre, Laurence ^d   Mandel, Jean Louis ^a,b,c   Piton, Amélie ^a,b   more..

^a UNIVERSITÉ DE STRASBOURG   (France)

^b l'alimentation et l'Environnement   (France)

^c UNIVERSITY HOSPITAL OF STRASBOURG   (France)

^d Medical University of Dijon   (France)

^e HÔPITAL ARNAUD DE VILLENEUVE   (France)

^f HOSPICES CIVILS DE LYON   (France)

^g HÔPITAL DE HAUTEPIERRE   (France)

^h ANGERS UNIVERSITY HOSPITAL   (France)

ⁱ UNIVERSITÉ DE BORDEAUX   (France)

^j ROUEN UNIVERSITY HOSPITAL   (France)

^k RENNES UNIVERSITY HOSPITAL   (France)

^l HÔTEL DIEU   (France)

^m NÎMES UNIVERSITY HOSPITAL   (France)

ⁿ AMIENS UNIVERSITY HOSPITAL   (France)

^o CENTRE HOSPITALIER   (France)

^p HÔPITAL SAINT VINCENT DE PAUL   (France)

^q REIMS UNIVERSITY HOSPITAL   (France)

^r NANTES UNIVERSITY HOSPITAL   (France)

more..

Author keywords

[No Author keywords available]

Indexed keywords

AMINE OXIDASE (FLAVIN CONTAINING) ISOENZYME A; DNA;

ADOLESCENT; ADULT; ARTICLE; AUTISM; AUTOSOMAL DOMINANT INHERITANCE; AUTOSOMAL RECESSIVE INHERITANCE; BIOINFORMATICS; CHILD; CLINICAL FEATURE; COGNITIVE DEFECT; COHORT ANALYSIS; DIAGNOSTIC TEST ACCURACY STUDY; DIAGNOSTIC VALUE; DNA LIBRARY; FALSE POSITIVE RESULT; FEMALE; FRAMESHIFT MUTATION; GENE FREQUENCY; GENE TARGETING; GENETIC ASSOCIATION; GENETIC CONSERVATION; GENETIC HETEROGENEITY; GENOTYPE PHENOTYPE CORRELATION; HIGH THROUGHPUT SEQUENCING; HUMAN; INFANT; INTELLECTUAL IMPAIRMENT; MAJOR CLINICAL STUDY; MALE; MISSENSE MUTATION; MOLECULAR DIAGNOSIS; MOLECULAR DIAGNOSTICS; MORBIDITY; NEWBORN; PATHOGENESIS; POINT MUTATION; PRIORITY JOURNAL; PROMOTER REGION; SEGREGATION ANALYSIS; STOP CODON; UROGENITAL TRACT MALFORMATION; X CHROMOSOME; DNA SEQUENCE; GENETICS; INTELLECTUAL DISABILITY; NUCLEOTIDE SEQUENCE; PRESCHOOL CHILD; PROCEDURES; YOUNG ADULT;

ADOLESCENT; ADULT; CHILD; CHILD, PRESCHOOL; DNA MUTATIONAL ANALYSIS; FEMALE; HIGH-THROUGHPUT NUCLEOTIDE SEQUENCING; HUMANS; INFANT; INFANT, NEWBORN; INTELLECTUAL DISABILITY; MALE; MOLECULAR DIAGNOSTIC TECHNIQUES; SEQUENCE ANALYSIS, DNA; YOUNG ADULT;

EID: 84925934363     PISSN: 00222593     EISSN: 14686244     Source Type: Journal    
DOI: 10.1136/jmedgenet-2014-102554     Document Type: Article

References (75)

1. Leonard H, Wen X. The epidemiology of mental retardation: challenges and opportunities in the new millennium. Ment Retard Dev Disabil Res Rev 2002;8:117-34.
2. Maulik PK, Mascarenhas MN, Mathers CD, Dua T, Saxena S. Prevalence of intellectual disability: a meta-analysis of population-based studies. Res Dev Disabil 2011;32:419-36.
3. de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 2012;367:1921-9.
4. Lubs HA, Stevenson RE, Schwartz CE. Fragile X and X-linked intellectual disability: four decades of discovery. Am J Hum Genet 2012;90:579-90.
5. Najmabadi H, Hu H, Garshasbi M, Zemojtel T, Abedini SS, Chen W, Hosseini M, Behjati F, Haas S, Jamali P, Zecha A, Mohseni M, Puttmann L, Vahid LN, Jensen C, Moheb LA, Bienek M, Larti F, Mueller I, Weissmann R, Darvish H, Wrogemann K, Hadavi V, Lipkowitz B, Esmaeeli-Nieh S, Wieczorek D, Kariminejad R, Firouzabadi SG, Cohen M, Fattahi Z, Rost I, Mojahedi F, Hertzberg C, Dehghan A, Rajab A, Banavandi MJ, Hoffer J, Falah M, Musante L, Kalscheuer V, Ullmann R, Kuss AW, Tzschach A, Kahrizi K, Ropers HH. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 2011;478:57-63.
6. Ropers HH. Genetics of early onset cognitive impairment. Annu Rev Genomics Hum Genet 2010;11:161-87.
7. Vissers LE, de Ligt J, Gilissen C, Janssen I, Steehouwer M, de Vries P, van Lier B, Arts P, Wieskamp N, del Rosario M, van Bon BW, Hoischen A, de Vries BB, Brunner HG, Veltman JA. A de novo paradigm for mental retardation. Nat Genet 2010;42:1109-12
8. Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, Albrecht B, Bartholdi D, Beygo J, Di Donato N, Dufke A, Cremer K, Hempel M, Horn D, Hoyer J, Joset P, Ropke A, Moog U, Riess A, Thiel CT, Tzschach A, Wiesener A, Wohlleber E, Zweier C, Ekici AB, Zink AM, Rump A, Meisinger C, Grallert H, Sticht H, Schenck A, Engels H, Rappold G, Schrock E, Wieacker P, Riess O, Meitinger T, Reis A, Strom TM. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 2012;380:1674-82.
9. Gilissen CH-KJ, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, Kwint M, Janssen IM, Hoischen A, Schenck A, Leach R, Klein R, Tearle R, Bo T, Pfundt R, Yntema HG, de Vries BB, Kleefstra T, Brunner HG, Vissers LE, Veltman JA. Genome sequencing identifies major causes of severe intellectual disability. Nature 2014;511:344-7.
10. Biancalana V, Beldjord C, Taillandier A, Szpiro-Tapia S, Cusin V, Gerson F, Philippe C, Mandel JL. Five years of molecular diagnosis of Fragile X syndrome (1997-2001): a collaborative study reporting 95% of the activity in France. Am J Med Genet A 2004;129A:218-24.
11. Rauch A, Hoyer J, Guth S, Zweier C, Kraus C, Becker C, Zenker M, Hüffmeier U, Thiel C, Rüschendorf F, Nürnberg P, Reis A, Trautmann U. Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. Am J Med Genet A 2006;140:2063-74.
12. van Karnebeek CD, Jansweijer MC, Leenders AG, Offringa M, Hennekam RC. Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness. Eur J Hum Genet 2005;13:6-25.
13. Redin C, Le Gras S, Mhamdi O, Geoffroy V, Stoetzel C, Vincent MC, Chiurazzi P, Lacombe D, Ouertani I, Petit F, Till M, Verloes A, Jost B, Chaabouni HB, Dollfus H, Mandel JL, Muller J. Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alstrom syndromes. J Med Genet 2012;49:502-12.
14. Piton A, Redin C, Mandel JL. XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing. Am J Hum Genet 2013;93:368-83.
15. Piton A, Jouan L, Rochefort D, Dobrzeniecka S, Lachapelle K, Dion PA, Gauthier J, Rouleau GA. Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals. Eur J Hum Genet 2013;21:749-56.
16. Archer HL, Whatley SD, Evans JC, Ravine D, Huppke P, Kerr A, Bunyan D, Kerr B, Sweeney E, Davies SJ, Reardon W, Horn J, MacDermot KD, Smith RA, Magee A, Donaldson A, Crow Y, Hermon G, Miedzybrodzka Z, Cooper DN, Lazarou L, Butler R, Sampson J, Pilz DT, Laccone F, Clarke AJ. Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients. J Med Genet 2006;43:451-6.
17. Lebo RV, Ikuta T, Milunsky JM, Milunsky A. Rett syndrome from quintuple and triple deletions within the MECP2 deletion hotspot region. Clin Genet 2001;59: 406-17.
18. Ravn K, Nielsen JB, Skjeldal OH, Kerr A, Hulten M, Schwartz M. Large genomic rearrangements in MECP2. Hum Mutat 2005;25:324.
19. Behnecke A, Hinderhofer K, Bartsch O, Numann A, Ipach ML, Damatova N, Haaf T, Dufke A, Riess O, Moog U. Intragenic deletions of IL1RAPL1: report of two cases and review of the literature. Am J Med Genet A 2011;155A:372-9.
20. Epi KC, Epilepsy Phenome/Genome P, Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, Epstein MP, Glauser T, Goldstein DB, Han Y, Heinzen EL, Hitomi Y, Howell KB, Johnson MR, Kuzniecky R, Lowenstein DH, Lu YF, Madou MR, Marson AG, Mefford HC, Esmaeeli Nieh S, O'Brien TJ, Ottman R, Petrovski S, Poduri A, Ruzzo EK, Scheffer IE, Sherr EH, Yuskaitis CJ, Abou-Khalil B, Alldredge BK, Bautista JF, Berkovic SF, Boro A, Cascino GD, Consalvo D, Crumrine P, Devinsky O, Dlugos D, Epstein MP, Fiol M, Fountain NB, French J, Friedman D, Geller EB, Glauser T, Glynn S, Haut SR, Hayward J, Helmers SL, Joshi S, Kanner A, Kirsch HE, Knowlton RC, Kossoff EH, Kuperman R, Kuzniecky R, Lowenstein DH, McGuire SM, Motika PV, Novotny EJ, Ottman R, Paolicchi JM, Parent JM, Park K, Poduri A, Scheffer IE, Shellhaas RA, Sherr EH, Shih JJ, Singh R, Sirven J, Smith MC, Sullivan J, Lin Thio L, Venkat A, Vining EP, Von Allmen GK, Weisenberg JL, Widdess-Walsh P, Winawer MR. De novo mutations in epileptic encephalopathies. Nature 2013;501:217-21.
21. Hamdan FF, Gauthier J, Araki Y, Lin DT, Yoshizawa Y, Higashi K, Park AR, Spiegelman D, Dobrzeniecka S, Piton A, Tomitori H, Daoud H, Massicotte C, Henrion E, Diallo O, Group SD, Shekarabi M, Marineau C, Shevell M, Maranda B, Mitchell G, Nadeau A, D'Anjou G, Vanasse M, Srour M, Lafreniere RG, Drapeau P, Lacaille JC, Kim E, Lee JR, Igarashi K, Huganir RL, Rouleau GA, Michaud JL. Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet 2011;88:306-16.
22. Shoubridge C, Tarpey PS, Abidi F, Ramsden SL, Rujirabanjerd S, Murphy JA, Boyle J, Shaw M, Gardner A, Proos A, Puusepp H, Raymond FL, Schwartz CE, Stevenson RE, Turner G, Field M, Walikonis RS, Harvey RJ, Hackett A, Futreal PA, Stratton MR, Gecz J. Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability. Nat Genet 2010;42:486-8.
23. Tran Mau-Them F, Willems M, Albrecht B, Sanchez E, Puechberty J, Endele S, Schneider A, Ruiz Pallares N, Missirian C, Rivier F, Girard M, Holder M, Manouvrier S, Touitou I, Lefort G, Sarda P, Moncla A, Drunat S, Wieczorek D, Genevieve D. Expanding the phenotype of IQSEC2 mutations: truncating mutations in severe intellectual disability. Eur J Hum Genet 2014;22:289-92.
24. Moller RS, Kubart S, Hoeltzenbein M, Heye B, Vogel I, Hansen CP, Menzel C, Ullmann R, Tommerup N, Ropers HH, Tumer Z, Kalscheuer VM. Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly. Am J Hum Genet 2008;82:1165-70.
25. van Bon BW, Hoischen A, Hehir-Kwa J, de Brouwer AP, Ruivenkamp C, Gijsbers AC, Marcelis CL, de Leeuw N, Veltman JA, Brunner HG, de Vries BB. Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly. Clin Genet 2011;79:296-9.
26. Yamamoto T, Shimojima K, Nishizawa T, Matsuo M, Ito M, Imai K. Clinical manifestations of the deletion of Down syndrome critical region including DYRK1A and KCNJ6. Am J Med Genet A 2011;155A:113-19.
27. Courcet JB, Faivre L, Malzac P, Masurel-Paulet A, Lopez E, Callier P, Lambert L, Lemesle M, Thevenon J, Gigot N, Duplomb L, Ragon C, Marle N, Mosca-Boidron AL, Huet F, Philippe C, Moncla A, Thauvin-Robinet C. The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy. J Med Genet 2012;49:731-6.
28. 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 JC, Darnell RB, Mardis ER, Wilson RK, Schatz MC, McCombie WR, Wigler M. De novo gene disruptions in children on the autistic spectrum. Neuron 2012;74:285-99.
29. O'Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, Carvill G, Kumar A, Lee C, Ankenman K, Munson J, Hiatt JB, Turner EH, Levy R, O'Day DR, Krumm N, Coe BP, Martin BK, Borenstein E, Nickerson DA, Mefford HC, Doherty D, Akey JM, Bernier R, Eichler EE, Shendure J. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 2012;338:1619-22.
30. 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, Malig 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;485:246-50.
31. Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, Gibbs RA, Eng CM. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 2013;369:1502-11.
32. Amiel J, Rio M, de Pontual L, Redon R, Malan V, Boddaert N, Plouin P, Carter NP, Lyonnet S, Munnich A, Colleaux L. Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction. Am J Hum Genet 2007;80:988-93.
33. Hamdan FF, Daoud H, Patry L, Dionne-Laporte A, Spiegelman D, Dobrzeniecka S, Rouleau GA, Michaud JL. Parent-child exome sequencing identifies a de novo truncating mutation in TCF4 in non-syndromic intellectual disability. Clin Genet 2013;83:198-200.
34. Bushby KM, Appleton R, Anderson LV, Welch JL, Kelly P, Gardner-Medwin D. Deletion status and intellectual impairment in Duchenne muscular dystrophy. Dev Med Child Neurol 1995;37:260-9.
35. Daoud F, Angeard N, Demerre B, Martie I, Benyaou R, Leturcq F, Cossee M, Deburgrave N, Saillour Y, Tuffery S, Urtizberea A, Toutain A, Echenne B, Frischman M, Mayer M, Desguerre I, Estournet B, Reveillere C, Penisson B, Cuisset JM, Kaplan JC, Heron D, Rivier F, Chelly J. Analysis of Dp71 contribution in the severity of mental retardation through comparison of Duchenne and Becker patients differing by mutation consequences on Dp71 expression. Hum Mol Genet 2009;18:3779-94.
36. Emery AE, Skinner R, Holloway S. A study of possible heterogeneity in Duchenne muscular dystrophy. Clin Genet 1979;15:444-9.
37. Kerr TP, Sewry CA, Robb SA, Roberts RG. Long mutant dystrophins and variable phenotypes: evasion of nonsense-mediated decay? Hum Genet 2001;109:402-7.
38. Taylor PJ, Betts GA, Maroulis S, Gilissen C, Pedersen RL, Mowat DR, Johnston HM, Buckley MF. Dystrophin gene mutation location and the risk of cognitive impairment in Duchenne muscular dystrophy. PLoS ONE;5:e8803.
39. Zellweger H, Niedermeyer E. Central nervous system manifestations in childhood muscular dystrophy (CMD). I. Psychometric and electroencephalographic findings. Ann Paediatr 1965;205:25-42.
40. de Brouwer AP, Nabuurs SB, Verhaart IE, Oudakker AR, Hordijk R, Yntema HG, Hordijk-Hos JM, Voesenek K, de Vries BB, van Essen T, Chen W, Hu H, Chelly J, den Dunnen JT, Kalscheuer VM, Aartsma-Rus AM, Hamel BC, van Bokhoven H, Kleefstra T. A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy. Eur J Hum Genet 2014;22:480-5.
41. Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 1993;262:578-80.
42. Piton A, Poquet H, Redin C, Masurel A, Lauer J, Muller J, Thevenon J, Herenger Y, Chancenotte S, Bonnet M, Pinoit JM, Huet F, Thauvin-Robinet C, Jaeger AS, Le Gras S, Jost B, Gerard B, Peoc'h K, Launay JM, Faivre L, Mandel JL. 20 ans apres: a second mutation in MAOA identified by targeted high-throughput sequencing in a family with altered behavior and cognition. Eur J Hum Genet 2014;22: 776-83.
43. Jamain S, Quach H, Betancur C, Rastam M, Colineaux C, Gillberg IC, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 2003;34:27-9.
44. Blasi F, Bacchelli E, Pesaresi G, Carone S, Bailey AJ, Maestrini E. Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection. Am J Med Genet B Neuropsychiatr Genet 2006;141B:220-1.
45. Gauthier J, Bonnel A, St-Onge J, Karemera L, Laurent S, Mottron L, Fombonne E, Joober R, Rouleau GA. NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec population. Am J Med Genet B Neuropsychiatr Genet 2005;132B:74-5.
46. Liu Y, Du Y, Liu W, Yang C, Wang H, Gong X. Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population. PLoS One 2013;8:e56639.
47. Vincent JB, Kolozsvari D, Roberts WS, Bolton PF, Gurling HM, Scherer SW. Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands. Am J Med Genet B Neuropsychiatr Genet 2004;129B:82-4.
48. Wermter AK, Kamp-Becker I, Strauch K, Schulte-Korne G, Remschmidt H. No evidence for involvement of genetic variants in the X-linked neuroligin genes NLGN3 and NLGN4X in probands with autism spectrum disorder on high functioning level. Am J Med Genet B Neuropsychiatr Genet 2008;147B: 535-7.
49. Yan J, Oliveira G, Coutinho A, Yang C, Feng J, Katz C, Sram J, Bockholt A, Jones IR, Craddock N, Cook EH Jr, Vicente A, Sommer SS. Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients. Mol Psychiatry 2005;10:329-32.
50. Ylisaukko-oja T, Rehnstrom K, Auranen M, Vanhala R, Alen R, Kempas E, Ellonen P, Turunen JA, Makkonen I, Riikonen R, Nieminen-von Wendt T, von Wendt L, Peltonen L, Jarvela I. Analysis of four neuroligin genes as candidates for autism. Eur J Hum Genet 2005;13:1285-92.
51. Muncke N, Jung C, Rudiger H, Ulmer H, Roeth R, Hubert A, Goldmuntz E, Driscoll D, Goodship J, Schon K, Rappold G. Missense mutations and gene interruption in PROSIT240, a novel TRAP240-like gene, in patients with congenital heart defect (transposition of the great arteries). Circulation 2003;108:2843-50.
52. Asadollahi R, Oneda B, Sheth F, Azzarello-Burri S, Baldinger R, Joset P, Latal B, Knirsch W, Desai S, Baumer A, Houge G, Andrieux J, Rauch A. Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability. Eur J Hum Genet 2013;21:1100-4.
53. van Haelst MM, Monroe GR, Duran K, van Binsbergen E, Breur JM, Giltay JC, van Haaften G. Further confirmation of the MED13L haploinsufficiency syndrome. Eur J Hum Genet 2014 Apr 30. Published Online First. doi: 10.1038/ejhg.2014.69
54. Vulto-van Silfhout AT, Rajamanickam S, Jensik PJ, Vergult S, de Rocker N, Newhall KJ, Raghavan R, Reardon SN, Jarrett K, McIntyre T, Bulinski J, Ownby SL, Huggenvik JI, McKnight GS, Rose GM, Cai X, Willaert A, Zweier C, Endele S, de Ligt J, van Bon BW, Lugtenberg D, de Vries PF, Veltman JA, van Bokhoven H, Brunner HG, Rauch A, de Brouwer AP, Carvill GL, Hoischen A, Mefford HC, Eichler EE, Vissers LE, Menten B, Collard MW, de Vries BB. Mutations Affecting the SAND Domain of DEAF1 Cause Intellectual Disability with Severe Speech Impairment and Behavioral Problems. Am J Hum Genet 2014;94:649-61.
55. Faqeih EA, Al-Owain M, Colak D, Kenana R, Al-Yafee Y, Al-Dosary M, Al-Saman A, Albalawi F, Al-Sarar D, Domiaty D, Daghestani M, Kaya N. Novel homozygous DEAF1 variant suspected in causing white matter disease, intellectual disability, and microcephaly. Am J Med Genet A 2014;164A:1565-70.
56. Albers CA, Paul DS, Schulze H, Freson K, Stephens JC, Smethurst PA, Jolley JD, Cvejic A, Kostadima M, Bertone P, Breuning MH, Debili N, Deloukas P, Favier R, Fiedler J, Hobbs CM, Huang N, Hurles ME, Kiddle G, Krapels I, Nurden P, Ruivenkamp CA, Sambrook JG, Smith K, Stemple DL, Strauss G, Thys C, van Geet C, Newbury-Ecob R, Ouwehand WH, Ghevaert C. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat Genet 2012;44:435-9, S1-2.
57. Unger S, Mainberger A, Spitz C, Bahr A, Zeschnigk C, Zabel B, Superti-Furga A, Morris-Rosendahl DJ. Filamin A mutation is one cause of FG syndrome. Am J Med Genet A 2007;143A:1876-9.
58. Salmi M, Bruneau N, Cillario J, Lozovaya N, Massacrier A, Buhler E, Cloarec R, Tsintsadze T, Watrin F, Tsintsadze V, Zimmer C, Villard C, Lafitte D, Cardoso C, Bao L, Lesca G, Rudolf G, Muscatelli F, Pauly V, Khalilov I, Durbec P, Ben-Ari Y, Burnashev N, Represa A, Szepetowski P. Tubacin prevents neuronal migration defects and epileptic activity caused by rat Srpx2 silencing in utero. Brain 2013;136(Pt 8):2457-73.
59. Sia GM, Clem RL, Huganir RL. The human language-associated gene SRPX2 regulates synapse formation and vocalization in mice. Science 2013;342:987-91.
60. Reinthaler EM, Lal D, Jurkowski W, Feucht M, Steinbock H, Gruber-Sedlmayr U, Ronen GM, Geldner J, Haberlandt E, Neophytou B, Hahn A, Altmuller J, Thiele H, Toliat MR, Lerche H, Nurnberg P, Sander T, Neubauer BA, Zimprich F. Analysis of ELP4, SRPX2, and interacting genes in typical and atypical rolandic epilepsy. Epilepsia 2014 Aug. Published Online First. doi: 10.1111/epi.12712.
61. Lesca G, Rudolf G, Bruneau N, Lozovaya N, Labalme A, Boutry-Kryza N, Salmi M, Tsintsadze T, Addis L, Motte J, Wright S, Tsintsadze V, Michel A, Doummar D, Lascelles K, Strug L, Waters P, de Bellescize J, Vrielynck P, de Saint Martin A, Ville D, Ryvlin P, Arzimanoglou A, Hirsch E, Vincent A, Pal D, Burnashev N, Sanlaville D, Szepetowski P. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet 2013;45:1061-6.
62. Griggs BL, Ladd S, Saul RA, DuPont BR, Srivastava AK. Dedicator of cytokinesis 8 is disrupted in two patients with mental retardation and developmental disabilities. Genomics 2008;91:195-202.
63. Laumonnier F, Holbert S, Ronce N, Faravelli F, Lenzner S, Schwartz CE, Lespinasse J, Van Esch H, Lacombe D, Goizet C, Phan-Dinh Tuy F, van Bokhoven H, Fryns JP, Chelly J, Ropers HH, Moraine C, Hamel BC, Briault S. Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate. J Med Genet 2005;42:780-6.
64. Yu HC, Sloan JL, Scharer G, Brebner A, Quintana AM, Achilly NP, Manoli I, Coughlin CR II, Geiger EA, Schneck U, Watkins D, Suormala T, Van Hove JL, Fowler B, Baumgartner MR, Rosenblatt DS, Venditti CP, Shaikh TH. An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1. Am J Hum Genet 2013;93:506-14.
65. Leen WG, Klepper J, Verbeek MM, Leferink M, Hofste T, van Engelen BG, Wevers RA, Arthur T, Bahi-Buisson N, Ballhausen D, Bekhof J, van Bogaert P, Carrilho I, Chabrol B, Champion MP, Coldwell J, Clayton P, Donner E, Evangeliou A, Ebinger F, Farrell K, Forsyth RJ, de Goede CG, Gross S, Grunewald S, Holthausen H, Jayawant S, Lachlan K, Laugel V, Leppig K, Lim MJ, Mancini G, Marina AD, Martorell L, McMenamin J, Meuwissen ME, Mundy H, Nilsson NO, Panzer A, Poll-The BT, Rauscher C, Rouselle CM, Sandvig I, Scheffner T, Sheridan E, Simpson N, Sykora P, Tomlinson R, Trounce J, Webb D, Weschke B, Scheffer H, Willemsen MA. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain 2010;133(Pt 3):655-70.
66. Girirajan S, Rosenfeld JA, Cooper GM, Antonacci F, Siswara P, Itsara A, Vives L, Walsh T, McCarthy SE, Baker C, Mefford HC, Kidd JM, Browning SR, Browning BL, Dickel DE, Levy DL, Ballif BC, Platky K, Farber DM, Gowans GC, Wetherbee JJ, Asamoah A, Weaver DD, Mark PR, Dickerson J, Garg BP, Ellingwood SA, Smith R, Banks VC, Smith W, McDonald MT, Hoo JJ, French BN, Hudson C, Johnson JP, Ozmore JR, Moeschler JB, Surti U, Escobar LF, El-Khechen D, Gorski JL, Kussmann J, Salbert B, Lacassie Y, Biser A, McDonald-McGinn DM, Zackai EH, Deardorff MA, Shaikh TH, Haan E, Friend KL, Fichera M, Romano C, Gecz J, DeLisi LE, Sebat J, King MC, Shaffer LG, Eichler EE. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet 2010;42:203-9.
67. Leblond CS, Heinrich J, Delorme R, Proepper C, Betancur C, Huguet G, Konyukh M, Chaste P, Ey E, Rastam M, Anckarsater H, Nygren G, Gillberg IC, Melke J, Toro R, Regnault B, Fauchereau F, Mercati O, Lemiere N, Skuse D, Poot M, Holt R, Monaco AP, Jarvela I, Kantojarvi K, Vanhala R, Curran S, Collier DA, Bolton P, Chiocchetti A, Klauck SM, Poustka F, Freitag CM, Waltes R, Kopp M, Duketis E, Bacchelli E, Minopoli F, Ruta L, Battaglia A, Mazzone L, Maestrini E, Sequeira AF, Oliveira B, Vicente A, Oliveira G, Pinto D, Scherer SW, Zelenika D, Delepine M, Lathrop M, Bonneau D, Guinchat V, Devillard F, Assouline B, Mouren MC, Leboyer M, Gillberg C, Boeckers TM, Bourgeron T. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genet 2012;8:e1002521.
68. Schaaf CP, Sabo A, Sakai Y, Crosby J, Muzny D, Hawes A, Lewis L, Akbar H, Varghese R, Boerwinkle E, Gibbs RA, Zoghbi HY. Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders. Hum Mol Genet 2011;20:3366-75.
69. Mandel JL, Chelly J. Monogenic X-linked mental retardation: is it as frequent as currently estimated? The paradox of the ARX (Aristaless X) mutations. Eur J Hum Genet 2004;12:689-93.
70. Nava C, Lamari F, Heron D, Mignot C, Rastetter A, Keren B, Cohen D, Faudet A, Bouteiller D, Gilleron M, Jacquette A, Whalen S, Afenjar A, Perisse D, Laurent C, Dupuits C, Gautier C, Gerard M, Huguet G, Caillet S, Leheup B, Leboyer M, Gillberg C, Delorme R, Bourgeron T, Brice A, Depienne C. Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE. Transl Psychiatry 2012;2:e179.
71. Tarpey PS, Smith R, Pleasance E, Whibley A, Edkins S, Hardy C, O'Meara S, Latimer C, Dicks E, Menzies A, Stephens P, Blow M, Greenman C, Xue Y, Tyler-Smith C, Thompson D, Gray K, Andrews J, Barthorpe S, Buck G, Cole J, Dunmore R, Jones D, Maddison M, Mironenko T, Turner R, Turrell K, Varian J, West S, Widaa S, Wray P, Teague J, Butler A, Jenkinson A, Jia M, Richardson D, Shepherd R, Wooster R, Tejada MI, Martinez F, Carvill G, Goliath R, de Brouwer AP, van Bokhoven H, Van Esch H, Chelly J, Raynaud M, Ropers HH, Abidi FE, Srivastava AK, Cox J, Luo Y, Mallya U, Moon J, Parnau J, Mohammed S, Tolmie JL, Shoubridge C, Corbett M, Gardner A, Haan E, Rujirabanjerd S, Shaw M, Vandeleur L, Fullston T, Easton DF, Boyle J, Partington M, Hackett A, Field M, Skinner C, Stevenson RE, Bobrow M, Turner G, Schwartz CE, Gecz J, Raymond FL, Futreal PA, Stratton MR. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat Genet 2009;41:535-43.
72. Simpson DA, Clark GR, Alexander S, Silvestri G, Willoughby CE. Molecular diagnosis for heterogeneous genetic diseases with targeted high-throughput DNA sequencing applied to retinitis pigmentosa. J Med Genet 2011;48:145-51.
73. Brownstein Z, Friedman LM, Shahin H, Oron-Karni V, Kol N, Abu Rayyan A, Parzefall T, Lev D, Shalev S, Frydman M, Davidov B, Shohat M, Rahile M, Lieberman S, Levy-Lahad E, Lee MK, Shomron N, King MC, Walsh T, Kanaan M, Avraham KB. Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in Middle Eastern families. Genome Biol 2011;12:R89.
74. Huang L, Jolly LA, Willis-Owen S, Gardner A, Kumar R, Douglas E, Shoubridge C, Wieczorek D, Tzschach A, Cohen M, Hackett A, Field M, Froyen G, Hu H, Haas SA, Ropers HH, Kalscheuer VM, Corbett MA, Gecz J. A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability. Am J Hum Genet 2012;91:694-702.
75. Gibbons RJ, Wada T, Fisher CA, Malik N, Mitson MJ, Steensma DP, Fryer A, Goudie DR, Krantz ID, Traeger-Synodinos J. Mutations in the chromatin-associated protein ATRX. Hum Mutat 2008;29:796-802.