Human Genetics

, Volume 134, Issue 9, pp 967–980 | Cite as

High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders

  • Tarunashree Yavarna
  • Nader Al-Dewik
  • Mariam Al-Mureikhi
  • Rehab Ali
  • Fatma Al-Mesaifri
  • Laila Mahmoud
  • Noora Shahbeck
  • Shenela Lakhani
  • Mariam AlMulla
  • Zafar Nawaz
  • Patrik Vitazka
  • Fowzan S. AlkurayaEmail author
  • Tawfeg Ben-OmranEmail author
Original Investigation


Clinical exome sequencing (CES) has become an increasingly popular diagnostic tool in patients with heterogeneous genetic disorders, especially in those with neurocognitive phenotypes. Utility of CES in consanguineous populations has not yet been determined on a large scale. A clinical cohort of 149 probands from Qatar with suspected Mendelian, mainly neurocognitive phenotypes, underwent CES from July 2012 to June 2014. Intellectual disability and global developmental delay were the most common clinical presentations but our cohort displayed other phenotypes, such as epilepsy, dysmorphism, microcephaly and other structural brain anomalies and autism. A pathogenic or likely pathogenic mutation, including pathogenic CNVs, was identified in 89 probands for a diagnostic yield of 60 %. Consanguinity and positive family history predicted a higher diagnostic yield. In 5 % (7/149) of cases, CES implicated novel candidate disease genes (MANF, GJA9, GLG1, COL15A1, SLC35F5, MAGE4, NEUROG1). CES uncovered two coexisting genetic disorders in 4 % (6/149) and actionable incidental findings in 2 % (3/149) of cases. Average time to diagnosis was reduced from 27 to 5 months. CES, which already has the highest diagnostic yield among all available diagnostic tools in the setting of Mendelian disorders, appears to be particularly helpful diagnostically in the highly consanguineous Middle Eastern population.


Intellectual Disability Diagnostic Yield Pathogenic Variant Neurocognitive Disorder High Diagnostic Yield 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank all families described in this paper and the healthcare providers who were involved in their care. We would also like to thank Mr. Patricio Santos Ayroso for his administrative support.

Supplementary material

439_2015_1575_MOESM1_ESM.pdf (215 kb)
Supplementary material 1 (PDF 214 kb)


  1. Abbasi-Moheb L, Mertel S, Gonsior M, Nouri-Vahid L, Kahrizi K, Cirak S, Wieczorek D, Motazacker MM, Esmaeeli-Nieh S, Cremer K, Weissmann R, Tzschach A, Garshasbi M, Abedini SS, Najmabadi H, Ropers HH, Sigrist SJ, Kuss AW (2012) Mutations in NSUN2 cause autosomal-recessive intellectual disability. Am J Hum Genet 90:847–855. doi: 10.1016/j.ajhg.2012.03.021 PubMedCentralPubMedCrossRefGoogle Scholar
  2. Akizu N, Shembesh NM, Ben-Omran T, Bastaki L, Al-Tawari A, Zaki MS, Koul R, Spencer E, Rosti RO, Scott E, Nickerson E, Gabriel S, da Gente G, Li J, Deardorff MA, Conlin LK, Horton MA, Zackai EH, Sherr EH, Gleeson JG (2013) Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia. Am J Hum Genet 92:392–400. doi: 10.1016/j.ajhg.2013.02.004 PubMedCentralPubMedCrossRefGoogle Scholar
  3. Aksentijevich I, Torosyan Y, Samuels J, Centola M, Pras E, Chae JJ, Oddoux C, Wood G, Azzaro MP, Palumbo G, Giustolisi R, Pras M, Ostrer H, Kastner DL (1999) Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet 64:949–962PubMedCentralPubMedCrossRefGoogle Scholar
  4. Alazami AM, Patel N, Shamseldin HE, Anazi S, Al-Dosari MS, Alzahrani F, Hijazi H, Alshammari M, Aldahmesh MA, Salih MA (2014) Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep 10:148–161PubMedCrossRefGoogle Scholar
  5. Andresen BS, Olpin S, Poorthuis BJ, Scholte HR, Vianey-Saban C, Wanders R, Ijlst L, Morris A, Pourfarzam M, Bartlett K, Baumgartner ER, deKlerk JB, Schroeder LD, Corydon TJ, Lund H, Winter V, Bross P, Bolund L, Gregersen N (1999) Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet 64:479–494. doi: 10.1086/302261 PubMedCentralPubMedCrossRefGoogle Scholar
  6. Aziz A, Harrop SP, Bishop NE (2011a) DIA1R is an X-linked gene related to deleted in Autism-1. PloS One 6:e14534. doi: 10.1371/journal.pone.0014534 PubMedCentralPubMedCrossRefGoogle Scholar
  7. Aziz A, Harrop SP, Bishop NE (2011b) Characterization of the deleted in autism 1 protein family: implications for studying cognitive disorders. PLoS One 6:e14547. doi: 10.1371/journal.pone.0014547 PubMedCentralPubMedCrossRefGoogle Scholar
  8. Ballmaier M, Germeshausen M, Schulze H, Cherkaoui K, Lang S, Gaudig A, Krukemeier S, Eilers M, Strauss G, Welte K (2001) c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia. Blood 97:139–146PubMedCrossRefGoogle Scholar
  9. Beaulieu CL, Majewski J, Schwartzentruber J, Samuels ME, Fernandez BA, Bernier FP, Brudno M, Knoppers B, Marcadier J, Dyment D, Adam S, Bulman DE, Jones SJ, Avard D, Nguyen MT, Rousseau F, Marshall C, Wintle RF, Shen Y, Scherer SW, Consortium FC, Friedman JM, Michaud JL, Boycott KM (2014) FORGE Canada Consortium: outcomes of a 2-year national rare-disease gene-discovery project. Am J Hum Genet 94:809–817. doi: 10.1016/j.ajhg.2014.05.003 PubMedCentralPubMedCrossRefGoogle Scholar
  10. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27:20–21. doi: 10.1038/83713 PubMedCrossRefGoogle Scholar
  11. Bercovich D, Elimelech A, Zlotogora J, Korem S, Yardeni T, Gal N, Goldstein N, Vilensky B, Segev R, Avraham S, Loewenthal R, Schwartz G, Anikster Y (2008) Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene. J Hum Genet 53:407–418. doi: 10.1007/s10038-008-0264-4 PubMedCrossRefGoogle Scholar
  12. Bick D, Dimmock D (2011) Whole exome and whole genome sequencing. Curr Opin Pediatr 23:594–600PubMedCrossRefGoogle Scholar
  13. Boutron A, Marabotti A, Facchiano A, Cheillan D, Zater M, Oliveira C, Costa C, Labrune P, Brivet M, French Galactosemia Working G (2012) Mutation spectrum in the French cohort of galactosemic patients and structural simulation of 27 novel missense variations. Mol Genet Metab 107:438–447. doi: 10.1016/j.ymgme.2012.07.025 PubMedCrossRefGoogle Scholar
  14. Boyken J, Grønborg M, Riedel D, Urlaub H, Jahn R, Chua JJE (2013) Molecular profiling of synaptic vesicle docking sites reveals novel proteins but few differences between glutamatergic and GABAergic synapses. Neuron 78:285–297PubMedCrossRefGoogle Scholar
  15. Cattanach BM, Barr JA, Beechey CV, Martin J, Noebels J, Jones J (1997) A candidate model for Angelman syndrome in the mouse. Mamm Genome 8:472–478PubMedCrossRefGoogle Scholar
  16. Chahrour MH, Yu TW, Lim ET, Ataman B, Coulter ME, Hill RS, Stevens CR, Schubert CR, Collaboration AAS, Greenberg ME, Gabriel SB, Walsh CA (2012) Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLoS Genet 8:e1002635. doi: 10.1371/journal.pgen.1002635 PubMedCentralPubMedCrossRefGoogle Scholar
  17. Chassaing N, Bourthoumieu S, Cossee M, Calvas P, Vincent MC (2006) Mutations in EDAR account for one-quarter of non-ED1-related hypohidrotic ectodermal dysplasia. Hum Mutat 27:255–259. doi: 10.1002/humu.20295 PubMedCrossRefGoogle Scholar
  18. Chauveau C, Rowell J, Ferreiro A (2014) A rising titan: TTN review and mutation update. Hum Mutat 35:1046–1059. doi: 10.1002/humu.22611 PubMedCrossRefGoogle Scholar
  19. Choi G, Kopplin LJ, Tester DJ, Will ML, Haglund CM, Ackerman MJ (2004) Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. Circulation 110:2119–2124. doi: 10.1161/01.CIR.0000144471.98080.CA PubMedCrossRefGoogle Scholar
  20. Dagoneau N, Scheffer D, Huber C, Al-Gazali LI, Di Rocco M, Godard A, Martinovic J, Raas-Rothschild A, Sigaudy S, Unger S, Nicole S, Fontaine B, Taupin JL, Moreau JF, Superti-Furga A, Le Merrer M, Bonaventure J, Munnich A, Legeai-Mallet L, Cormier-Daire V (2004) Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome. Am J Hum Genet 74:298–305. doi: 10.1086/381715 PubMedCentralPubMedCrossRefGoogle Scholar
  21. el El-Harith HA, Roesl C, Ballmaier M, Germeshausen M, Frye-Boukhriss H, von Neuhoff N, Becker C, Nurnberg G, Nurnberg P, Ahmed MA, Hubener J, Schmidtke J, Welte K, Stuhrmann M (2009) Familial thrombocytosis caused by the novel germ-line mutation p.Pro106Leu in the MPL gene. Br J Haematol 144:185–194. doi: 10.1111/j.1365-2141.2008.07430.x CrossRefGoogle Scholar
  22. England J, Loughna S (2013) Heavy and light roles: myosin in the morphogenesis of the heart. Cell Mol Life Sci 70:1221–1239. doi: 10.1007/s00018-012-1131-1 PubMedCentralPubMedCrossRefGoogle Scholar
  23. Falsaperla R, Pavone L, Fichera M, Striano P, Pavone P (2012) Apneic crises: a clue for MECP2 testing in severe neonatal hypotonia-respiratory failure. Eur J Paediatr Neurol 16:744–748. doi: 10.1016/j.ejpn.2012.03.001 PubMedCrossRefGoogle Scholar
  24. Gibbons RJ, Bachoo S, Picketts DJ, Aftimos S, Asenbauer B, Bergoffen J, Berry SA, Dahl N, Fryer A, Keppler K, Kurosawa K, Levin ML, Masuno M, Neri G, Pierpont ME, Slaney SF, Higgs DR (1997) Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain. Nat Genet 17:146–148. doi: 10.1038/ng1097-146 PubMedCrossRefGoogle Scholar
  25. Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, Kwint M, Janssen IM, Hoischen A, Schenck A (2014) Genome sequencing identifies major causes of severe intellectual disability. Nature 511(7509):344–347Google Scholar
  26. Gonatas J, Mezitis S, Stieber A, Fleischer B, Gonatas N (1989) MG-160. A novel sialoglycoprotein of the medial cisternae of the Golgi apparatus [published erratum appears in J Biol Chem 1989 Mar 5; 264 (7): 4264]. J Biol Chem 264:646–653PubMedGoogle Scholar
  27. Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O’Daniel JM, Ormond KE (2013) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 15:565–574PubMedCentralPubMedCrossRefGoogle Scholar
  28. Guldberg P, Rey F, Zschocke J, Romano V, Francois B, Michiels L, Ullrich K, Hoffmann GF, Burgard P, Schmidt H, Meli C, Riva E, Dianzani I, Ponzone A, Rey J, Guttler F (1998) A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. Am J Hum Genet 63:71–79. doi: 10.1086/301920 PubMedCentralPubMedCrossRefGoogle Scholar
  29. Gulsuner S, Walsh T, Watts AC, Lee MK, Thornton AM, Casadei S, Rippey C, Shahin H, Consortium on the Genetics of S, Group PS, Nimgaonkar VL, Go RC, Savage RM, Swerdlow NR, Gur RE, Braff DL, King MC, McClellan JM (2013) Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 154:518–529. doi: 10.1016/j.cell.2013.06.049 PubMedCentralPubMedCrossRefGoogle Scholar
  30. 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 (2011) Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet 88:306–316. doi: 10.1016/j.ajhg.2011.02.001 PubMedCentralPubMedCrossRefGoogle Scholar
  31. Harakalova M, van den Boogaard MJ, Sinke R, van Lieshout S, van Tuil MC, Duran K, Renkens I, Terhal PA, de Kovel C, Nijman IJ, van Haelst M, Knoers NV, van Haaften G, Kloosterman W, Hennekam RC, Cuppen E, Ploos van Amstel HK (2012) X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face. J Med Genet 49:539–543. doi: 10.1136/jmedgenet-2012-100921 PubMedCrossRefGoogle Scholar
  32. Harlalka GV, Baple EL, Cross H, Kuhnle S, Cubillos-Rojas M, Matentzoglu K, Patton MA, Wagner K, Coblentz R, Ford DL, Mackay DJ, Chioza BA, Scheffner M, Rosa JL, Crosby AH (2013) Mutation of HERC2 causes developmental delay with Angelman-like features. J Med Genet 50:65–73. doi: 10.1136/jmedgenet-2012-101367 PubMedCrossRefGoogle Scholar
  33. Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG, Seidman CE (2012) Truncations of titin causing dilated cardiomyopathy. N Engl J Med 366:619–628. doi: 10.1056/NEJMoa1110186 PubMedCentralPubMedCrossRefGoogle Scholar
  34. 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 (2012) De novo gene disruptions in children on the autistic spectrum. Neuron 74:285–299. doi: 10.1016/j.neuron.2012.04.009 PubMedCentralPubMedCrossRefGoogle Scholar
  35. Jamal SM, Yu JH, Chong JX, Dent KM, Conta JH, Tabor HK, Bamshad MJ (2013) Practices and policies of clinical exome sequencing providers: analysis and implications. Am J Med Genet Part A 161:935–950CrossRefGoogle Scholar
  36. Jung C, Dagoneau N, Baujat G, Le Merrer M, David A, Di Rocco M, Hamel B, Megarbane A, Superti-Furga A, Unger S, Munnich A, Cormier-Daire V (2010) Stuve-Wiedemann syndrome: long-term follow-up and genetic heterogeneity. Clin Genet 77:266–272. doi: 10.1111/j.1399-0004.2009.01314.x PubMedCrossRefGoogle Scholar
  37. Karmous-Benailly H, Martinovic J, Gubler MC, Sirot Y, Clech L, Ozilou C, Auge J, Brahimi N, Etchevers H, Detrait E, Esculpavit C, Audollent S, Goudefroye G, Gonzales M, Tantau J, Loget P, Joubert M, Gaillard D, Jeanne-Pasquier C, Delezoide AL, Peter MO, Plessis G, Simon-Bouy B, Dollfus H, Le Merrer M, Munnich A, Encha-Razavi F, Vekemans M, Attie-Bitach T (2005) Antenatal presentation of Bardet-Biedl syndrome may mimic Meckel syndrome. Am J Hum Genet 76:493–504. doi: 10.1086/428679 PubMedCentralPubMedCrossRefGoogle Scholar
  38. Kathiravel U, Keyser B, Hoffjan S, Kotting J, Muller M, Sivalingam S, Bonin M, Arslan-Kirchner M, von Kodolitsch Y, Binner P, Scheffold T, Stuhrmann M, Waldmuller S (2013) High-density oligonucleotide-based resequencing assay for mutations causing syndromic and non-syndromic forms of thoracic aortic aneurysms and dissections. Mol Cell Probes 27:103–108. doi: 10.1016/j.mcp.2012.10.002 PubMedCrossRefGoogle Scholar
  39. Lange S, Xiang F, Yakovenko A, Vihola A, Hackman P, Rostkova E, Kristensen J, Brandmeier B, Franzen G, Hedberg B, Gunnarsson LG, Hughes SM, Marchand S, Sejersen T, Richard I, Edstrom L, Ehler E, Udd B, Gautel M (2005) The kinase domain of titin controls muscle gene expression and protein turnover. Science 308:1599–1603. doi: 10.1126/science.1110463 PubMedCrossRefGoogle Scholar
  40. Lancelot M-E, Germain A, Antonio A, Michiels C, Saraiva J-P, Letexier M, Sahel J-A, Bhattacharya SS, Zeitz C (2012) Development and application of a next-generation-sequencing (NGS) approach to detect known and novel gene defects underlying retinal diseases. Orphanet J Rare Dis 7:8. doi: 10.1186/1750-1172-7-8
  41. Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, Das K, Toy T, Harry B, Yourshaw M (2014) Clinical exome sequencing for genetic identification of rare mendelian disorders. JAMA 312:1880–1887PubMedCentralPubMedCrossRefGoogle Scholar
  42. Lindholm P, Saarma M (2010) Novel CDNF/MANF family of neurotrophic factors. Dev Neurobiol 70:360–371PubMedGoogle Scholar
  43. Lubbehusen J, Thiel C, Rind N, Ungar D, Prinsen BH, de Koning TJ, van Hasselt PM, Korner C (2010) Fatal outcome due to deficiency of subunit 6 of the conserved oligomeric Golgi complex leading to a new type of congenital disorders of glycosylation. Hum Mol Genet 19:3623–3633. doi: 10.1093/hmg/ddq278 PubMedCrossRefGoogle Scholar
  44. Ma Q, Chen Z, Barrantes IdB, Luis de la Pompa J, Anderson DJ (1998) neurogenin1 is essential for the determination of neuronal precursors for proximal cranial sensory ganglia. Neuron 20:469–482PubMedCrossRefGoogle Scholar
  45. Malan V, Rajan D, Thomas S, Shaw AC, Louis Dit Picard H, Layet V, Till M, van Haeringen A, Mortier G, Nampoothiri S, Puseljic S, Legeai-Mallet L, Carter NP, Vekemans M, Munnich A, Hennekam RC, Colleaux L, Cormier-Daire V (2010) Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome. Am J Hum Genet 87:189–198. doi: 10.1016/j.ajhg.2010.07.001 PubMedCentralPubMedCrossRefGoogle Scholar
  46. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ (2010) Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Human Genet 86:749–764CrossRefGoogle Scholar
  47. Monreal AW, Ferguson BM, Headon DJ, Street SL, Overbeek PA, Zonana J (1999) Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat Genet 22:366–369. doi: 10.1038/11937 PubMedCrossRefGoogle Scholar
  48. Mootha VK, Lepage P, Miller K, Bunkenborg J, Reich M, Hjerrild M, Delmonte T, Villeneuve A, Sladek R, Xu F, Mitchell GA, Morin C, Mann M, Hudson TJ, Robinson B, Rioux JD, Lander ES (2003) Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc Natl Acad Sci U S A 100:605–610. doi: 10.1073/pnas.242716699 PubMedCentralPubMedCrossRefGoogle Scholar
  49. Morin C, Mitchell G, Larochelle J, Lambert M, Ogier H, Robinson BH, De Braekeleer M (1993) Clinical, metabolic, and genetic aspects of cytochrome C oxidase deficiency in Saguenay-Lac-Saint-Jean. Am J Hum Genet 53:488–496PubMedCentralPubMedGoogle Scholar
  50. Muller J, Stoetzel C, Vincent MC, Leitch CC, Laurier V, Danse JM, Helle S, Marion V, Bennouna-Greene V, Vicaire S, Megarbane A, Kaplan J, Drouin-Garraud V, Hamdani M, Sigaudy S, Francannet C, Roume J, Bitoun P, Goldenberg A, Philip N, Odent S, Green J, Cossee M, Davis EE, Katsanis N, Bonneau D, Verloes A, Poch O, Mandel JL, Dollfus H (2010) Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease. Hum Genet 127:583–593. doi: 10.1007/s00439-010-0804-9 PubMedCentralPubMedCrossRefGoogle Scholar
  51. 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 (2011) Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478:57–63. doi: 10.1038/nature10423 PubMedCrossRefGoogle Scholar
  52. Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, Bunda S, Finklestein JZ, Sakamoto KM, Gorr TA, Mehta P, Schmid I, Kropshofer G, Corbacioglu S, Lang PJ, Klein C, Schlegel PG, Heinzmann A, Schneider M, Stary J, van den Heuvel-Eibrink MM, Hasle H, Locatelli F, Sakai D, Archambeault S, Chen L, Russell RC, Sybingco SS, Ohh M, Braun BS, Flotho C, Loh ML (2010) Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet 42:794–800. doi: 10.1038/ng.641 PubMedCentralPubMedCrossRefGoogle Scholar
  53. Park DH, Hong SJ, Salinas RD, Liu SJ, Sun SW, Sgualdino J, Testa G, Matzuk MM, Iwamori N, Lim DA (2014) Activation of neuronal gene expression by the JMJD3 demethylase is required for postnatal and adult brain neurogenesis. Cell Rep 8:1290–1299. doi: 10.1016/j.celrep.2014.07.060 PubMedCrossRefGoogle Scholar
  54. Pavone P, Taibi R, Lionetti E, Incorpora G, Fisher CA (2010) First case of dizygous twins with X-linked alpha-thalassemia/mental retardation syndrome showing wide clinical variability. Pediatr Int 52:e72–e75. doi: 10.1111/j.1442-200X.2010.03048.x PubMedCrossRefGoogle Scholar
  55. Plaisancie J, Bailleul-Forestier I, Gaston V, Vaysse F, Lacombe D, Holder-Espinasse M, Abramowicz M, Coubes C, Plessis G, Faivre L, Demeer B, Vincent-Delorme C, Dollfus H, Sigaudy S, Guillen-Navarro E, Verloes A, Jonveaux P, Martin-Coignard D, Colin E, Bieth E, Calvas P, Chassaing N (2013) Mutations in WNT10A are frequently involved in oligodontia associated with minor signs of ectodermal dysplasia. Am J Med Genet A 161A:671–678. doi: 10.1002/ajmg.a.35747 PubMedCrossRefGoogle Scholar
  56. Puffenberger EG, Jinks RN, Wang H, Xin B, Fiorentini C, Sherman EA, Degrazio D, Shaw C, Sougnez C, Cibulskis K, Gabriel S, Kelley RI, Morton DH, Strauss KA (2012) A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder. Hum Mutat 33:1639–1646. doi: 10.1002/humu.22237 PubMedCrossRefGoogle Scholar
  57. Rehm HL (2013) Disease-targeted sequencing: a cornerstone in the clinic. Nature Rev Genet 14:295–300PubMedCentralPubMedCrossRefGoogle Scholar
  58. Richards S, CAP NA, Bale S, Bick D, Das S, Gastier J, Grody WW, Hegde M, Spector E, CAP KV (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the american college of medical genetics and genomics and the association for molecular pathology authors/affiliations. Genet Med 17(5):405–23Google Scholar
  59. Santen GW, Aten E, Sun Y, Almomani R, Gilissen C, Nielsen M, Kant SG, Snoeck IN, Peeters EA, Hilhorst-Hofstee Y, Wessels MW, den Hollander NS, Ruivenkamp CA, van Ommen GJ, Breuning MH, den Dunnen JT, van Haeringen A, Kriek M (2012) Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nat Genet 44:379–380. doi: 10.1038/ng.2217 PubMedCrossRefGoogle Scholar
  60. Shaag A, Saada A, Berger I, Mandel H, Joseph A, Feigenbaum A, Elpeleg ON (1999) Molecular basis of lipoamide dehydrogenase deficiency in Ashkenazi Jews. Am J Med Genet 82:177–182PubMedCrossRefGoogle Scholar
  61. Shaheen R, Ansari S, Alshammari MJ, Alkhalidi H, Alrukban H, Eyaid W, Alkuraya FS (2013) A novel syndrome of hypohidrosis and intellectual disability is linked to COG6 deficiency. J Med Genet 50:431–436. doi: 10.1136/jmedgenet-2013-101527 PubMedCrossRefGoogle Scholar
  62. Sobrido MJ, Coppola G, Oliveira J, Hopfer S, Geschwind DH (2004) Primary Familial Brain Calcification. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K (eds) GeneReviews® [Internet]. University of Washington, Seattle, WA, 1993–2015Google Scholar
  63. Spiekerkoetter U (2010) Mitochondrial fatty acid oxidation disorders: clinical presentation of long-chain fatty acid oxidation defects before and after newborn screening. J Inherit Metab Dis 33:527–532. doi: 10.1007/s10545-010-9090-x PubMedCrossRefGoogle Scholar
  64. Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT (2000) Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 102:1178–1185PubMedCrossRefGoogle Scholar
  65. Stenson PD, Mort M, Ball EV, Howells K, Phillips AD, Thomas NS, Cooper DN (2009) The Human Gene Mutation Database: 2008 update. Genome Med 1:13. doi: 10.1186/gm13 PubMedCentralPubMedCrossRefGoogle Scholar
  66. Stevens E, Carss KJ, Cirak S, Foley AR, Torelli S, Willer T, Tambunan DE, Yau S, Brodd L, Sewry CA, Feng L, Haliloglu G, Orhan D, Dobyns WB, Enns GM, Manning M, Krause A, Salih MA, Walsh CA, Hurles M, Campbell KP, Manzini MC, Consortium UK, Stemple D, Lin YY, Muntoni F (2013) Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of alpha-dystroglycan. Am J Hum Genet 92:354–365. doi: 10.1016/j.ajhg.2013.01.016 PubMedCentralPubMedCrossRefGoogle Scholar
  67. Tao G, Levay AK, Peacock JD, Huk DJ, Both SN, Purcell NH, Pinto JR, Galantowicz ML, Koch M, Lucchesi PA (2012) Collagen XIV is important for growth and structural integrity of the myocardium. J Mol Cell Cardiol 53:626–638PubMedCentralPubMedCrossRefGoogle Scholar
  68. Tester DJ, Will ML, Haglund CM, Ackerman MJ (2005) Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm 2:507–517. doi: 10.1016/j.hrthm.2005.01.020 PubMedCrossRefGoogle Scholar
  69. Tschernutter M, Jenkins SA, Waseem NH, Saihan Z, Holder GE, Bird AC, Bhattacharya SS, Ali RR, Webster AR (2006) Clinical characterisation of a family with retinal dystrophy caused by mutation in the Mertk gene. Br J Ophthalmol 90:718–723. doi: 10.1136/bjo.2005.084897 PubMedCentralPubMedCrossRefGoogle Scholar
  70. Tucker T, Marra M, Friedman JM (2009) Massively parallel sequencing: the next big thing in genetic medicine. Am J Human Genet 85:142–154CrossRefGoogle Scholar
  71. Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z (2013) Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 369:1502–1511PubMedCentralPubMedCrossRefGoogle Scholar
  72. Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, Ward P, Braxton A, Wang M, Buhay C (2014) Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 312:1870–1879PubMedCentralPubMedCrossRefGoogle Scholar
  73. Wan X, Chen S, Sadeghpour A, Wang Q, Kirsch GE (2001) Accelerated inactivation in a mutant Na(+) channel associated with idiopathic ventricular fibrillation. Am J Physiol Heart Circ Physiol 280:H354–H360PubMedGoogle Scholar
  74. Zahrani F, Aldahmesh MA, Alshammari MJ, Al-Hazzaa SA, Alkuraya FS (2013) Mutations in c12orf57 cause a syndromic form of colobomatous microphthalmia. Am J Hum Genet 92:387–391. doi: 10.1016/j.ajhg.2013.01.008 PubMedCentralPubMedCrossRefGoogle Scholar
  75. Zareba W, Moss AJ, Sheu G, Kaufman ES, Priori S, Vincent GM, Towbin JA, Benhorin J, Schwartz PJ, Napolitano C, Hall WJ, Keating MT, Qi M, Robinson J, Andrews ML, International Lqts Registry UoRRNY (2003) Location of mutation in the KCNQ1 and phenotypic presentation of long QT syndrome. J Cardiovasc Electrophysiol 14:1149–1153PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Tarunashree Yavarna
    • 1
  • Nader Al-Dewik
    • 1
  • Mariam Al-Mureikhi
    • 1
  • Rehab Ali
    • 1
  • Fatma Al-Mesaifri
    • 1
  • Laila Mahmoud
    • 1
  • Noora Shahbeck
    • 1
  • Shenela Lakhani
    • 1
  • Mariam AlMulla
    • 1
  • Zafar Nawaz
    • 2
  • Patrik Vitazka
    • 3
  • Fowzan S. Alkuraya
    • 4
    • 5
    Email author
  • Tawfeg Ben-Omran
    • 1
    • 6
    Email author
  1. 1.Clinical and Metabolic Genetics, Department of PediatricsHamad Medical CorporationDohaQatar
  2. 2.Cytogenetics and Molecular Cytogenetics, Department of Pathology and Laboratory MedicineHamad Medical CorporationDohaQatar
  3. 3.GeneDxGaithersburgUSA
  4. 4.Developmental Genetics Unit, Department of Genetics, Research CenterKing Faisal Specialist Hospital and Research CenterRiyadhSaudi Arabia
  5. 5.Department of Anatomy and Cell Biology, College of MedicineAlfaisal UniversityRiyadhSaudi Arabia
  6. 6.Weill Cornell Medical CollegeAl-RayyanQatar

Personalised recommendations