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Exoom-sequencing in de diagnostiek van ontwikkelingsachterstand/verstandelijke beperking

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Tijdschrift voor Kindergeneeskunde

Samenvatting

Onverklaarde ontwikkelingsachterstand/verstandelijke beperking (VB) is een van de belangrijkste redenen voor verwijzing naar de kinderarts en/of klinisch geneticus. De meeste ernstige vormen zijn genetisch bepaald. Naar schatting wordt de meerderheid verklaard door de novo genmutaties en chromosoomafwijkingen. Wanneer de patiënt geen klinisch herkenbaar beeld heeft, wordt doorgaans eerst chromosomenonderzoek met array-analyse ingezet. Wanneer er wel een klinisch herkenbaar beeld is, vindt gericht DNA-onderzoek van vaak meerdere genen plaats. Op indicatie vindt screenend metabool onderzoek plaats. Indien bovengenoemde onderzoeken geen diagnose opleveren, komt een deel van de patiënten sinds kort in aanmerking voor exoom-sequencing, waarmee de coderende delen van vrijwel alle genen tegelijkertijd onderzocht worden. De eerste diagnostische studies, bij patiënten zonder klinisch herkenbaar beeld en met een normale uitslag van de array-analyse, laten zien dat de opbrengst van dit onderzoek tussen de 16 en 55% ligt. Naast mutaties in bekende genen, gaat het hierbij ook om mutaties in nieuwe (kandidaat-) genen voor VB. Op korte termijn zal het tevens mogelijk worden om in de data verkregen met exoom-sequencing veranderingen in het aantal kopieën van (gedeelten van) chromosomen betrouwbaar te detecteren, waardoor in de nabije toekomst arrayanalyse als onderzoek van eerste keuze zal komen te vervallen. Het grote voordeel hiervan is dat met één test zowel chromosoomafwijkingen als monogene afwijkingen opgespoord kunnen worden, hoewel men zich wel moet realiseren dat ook met deze test niet alle genetische afwijkingen opgespoord kunnen worden. Het is daarnaast van belang om vóór aanvraag van het onderzoek expliciet de kans op detectie van onbekende varianten of toevalsbevindingen te bespreken.

Summary

Unexplained developmental delay/intellectual disability (ID) is one of the main reasons for referral to the pediatrician and/or clinical geneticist. Most severe forms have a single genetic cause. It is assumed that the majority can be explained by de novo gene mutations and chromosomal aberrations. At present, in most clinical diagnostic centers, array analysis is used as the first tier diagnostic test in individuals without a clinical recognizable ID syndrome. In patients with a clinical recognizable phenotype, specific DNA diagnostic tests, mostly of several genes, are requested. On indication, a metabolic screen is requested. A subset of the patients who remain undiagnosed after these diagnostic tests, is now a candidate for exome sequencing, which enables the unraveling of the coding parts of almost all genes in one single test. The first diagnostic studies in patients without a clinical recognizable syndrome and with normal results of array analysis, show that the diagnostic yield of this test may be 16-55%. These numbers include both mutations in known genes and novel (candidate) genes for ID. Furthermore, ongoing progress in technologies will enable the identification of copy number changes of (part of ) the chromosomes in exome data. Therefore, in the near future, exome sequencing will replace genome-wide chromosomal analysis as the first tier test. Major advantage is that both chromosomal aberrations and monogenic mutations can be detected by one single test. Of note, this test does not detect all genetic aberrations either. In addition, the possible identification of unknown variants and unsolicited findings should be explicitly discussed in the pretest counseling.

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Literatuur

  1. Heber R. A manual on terminology and classification in mental retardation. Am J Ment Defic. 1959;Suppl 64:1–111.

    PubMed  Google Scholar 

  2. Heber R. Modifications in the manual on terminology and classification in mental retardation. Am J Ment Defic. 1961;65:499–500.

    CAS  PubMed  Google Scholar 

  3. Schalock RL, Luckasson RA, Shogren KA, et al. The renaming of mental retardation: understanding the change to the term intellectual disability. Intellect Dev Disabil. 2007;45:116–24.

    Article  PubMed  Google Scholar 

  4. Schalock RL, Borthwick-Duffy SA, Bradley VJ, et al. Intellectual disability: Definition, classification, and systems of supports. Vol. 11.Washington: American Association on Intellectual and Developmental Disabilities, 2010.

    Google Scholar 

  5. Tassé MJ. What’s in a name? Intellect Dev Disabil. 2013;51:113–6.

    Article  PubMed  Google Scholar 

  6. Zigler E. Familial mental retardation: a continuing dilemma. Science. 1967;155:292–8.

    Article  CAS  PubMed  Google Scholar 

  7. Ropers HH. Genetics of early onset cognitive impairment. Annu Rev Genomics Hum Genet. 2010; 11:161–87.

    Article  CAS  PubMed  Google Scholar 

  8. Ras M, Woittiez I, Kempen H van, et al. Steeds meer verstandelijk gehandicapten? Ontwikkelingen in vraag en gebruik van zorg voor verstandelijk gehandicapten 1998–2008. Den Haag: Sociaal en Cultureel Planbureau, 2010.

    Google Scholar 

  9. Karnebeek CD van, Scheper FY, Abeling NG, et al. Etiology of mental retardation in children referred to a tertiary care center: a prospective study. Am J Ment Retard. 2005;110:253–67.

    Article  PubMed  Google Scholar 

  10. Stevenson RE, Procopio-Allen AM, Schroer RJ, Collins JS. Genetic syndromes among individuals with mental retardation. Am J Med Genet A. 2003; 123:29–32.

    Article  Google Scholar 

  11. Rauch A, Hoyer J, Guth S, et al. Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. Am J Med Genet A. 2006;140:2063–74.

    Article  PubMed  Google Scholar 

  12. Buggenhout GJ van, Ravenswaaij-Arts C van, Mieloo H, et al. Dysmorphology and mental retardation: molecular cytogenetic studies in dysmorphic mentally retarded patients. Ann Genet. 2001;44:89–92.

    Article  PubMed  Google Scholar 

  13. Michelson DJ, Shevell MI, Sherr EH, et al. Evidence report: Genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2011;77:1629–35.

    Article  CAS  PubMed  Google Scholar 

  14. Karnebeek CD van, Jansweijer MC, Leenders AG, et al. Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness. Eur J Hum Genet. 2005;13:6–25.

    Article  PubMed  Google Scholar 

  15. Moog U. The outcome of diagnostic studies on the etiology of mental retardation: considerations on the classification of the causes. Am J Med Genet A. 2005;137:228–31.

    Article  PubMed  Google Scholar 

  16. Hochstenbach P. Cytogenetische diagnostiek bij kinderen met een onverklaarde verstandelijke handicap. 50 jaar onderzoek naar oorzaken van verstandelijke handicaps. Capita Selecta. De Werkgroep ter bestudering van somatische oorzaken van zwakzinnigheid 2008. p. 80–91.

  17. Knight SJ, Regan R, Nicod A, et al. Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet. 1999;354: 1676–81.

    Article  CAS  PubMed  Google Scholar 

  18. Koolen DA, Nillesen WM, Versteeg MH, et al. Screening for subtelomeric rearrangements in 210 patients with unexplained mental retardation using multiplex ligation dependent probe amplification (MLPA). J Med Genet. 2004;41:892–9.

    Article  CAS  PubMed  Google Scholar 

  19. Crotwell PL, Hoyme HE. Advances in whole-genome genetic testing: from chromosomes to microarrays. Curr Probl Pediatr Adolesc Health Care. 2012;42:47–73.

    Article  PubMed  Google Scholar 

  20. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749–64.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Hochstenbach R, Binsbergen E van, Engelen J, et al. Array analysis and karyotyping: workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands. Eur J Med Genet. 2009;52:161–9.

    Article  PubMed  Google Scholar 

  22. Slavotinek AM. Novel microdeletion syndromes detected by chromosome microarrays. Hum Genet. 2008;124:1–17.

    Article  CAS  PubMed  Google Scholar 

  23. Kleefstra T, Smidt M, Banning MJ, et al. Disruption of the gene Euchromatin Histone Methyl Transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome. J Med Genet. 2005;42:299–306.

    Article  CAS  PubMed  Google Scholar 

  24. Kleefstra T, Zelst-Stams WA van, Nillesen WM, et al. Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. J Med Genet. 2009;46:598–606.

    Article  CAS  PubMed  Google Scholar 

  25. Willemsen MH, Fernandez BA, Bacino CA, et al. Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the novel 16q24.3 microdeletion syndrome. Eur J Hum Genet. 2010;18:429–35.

    Article  CAS  PubMed  Google Scholar 

  26. Zweier M, Gregor A, Zweier C, et al. Mutations in MEF2 C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression. Hum Mutat. 2010;31:722–33.

    Article  CAS  PubMed  Google Scholar 

  27. Sagoo GS, Butterworth AS, Sanderson S, et al. Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta-analysis of 19 studies and 13,926 subjects. Genet Med. 2009;11: 139–46.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. 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.

    Article  PubMed  Google Scholar 

  31. Ng SB, Bigham AW, Buckingham KJ, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010;42:790–3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Hoischen A, Bon BW van, Gilissen C, et al. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nat Genet. 2010;42:483–5.

    Article  CAS  PubMed  Google Scholar 

  33. Hoischen A, Bon BW van, Rodríguez-Santiago B, et al. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. Nat Genet. 2011;43:729–31.

    Article  CAS  PubMed  Google Scholar 

  34. Sirmaci A, Spiliopoulos M, Brancati F, et al. Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia. Am J Hum Genet. 2011;89:289–94.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Santen GW, Aten E, Sun Y, et al. Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nat Genet. 2012;44: 379–80.

    Article  CAS  PubMed  Google Scholar 

  36. Bon BW van, Gilissen C, Grange DK, et al. Cantu syndrome is caused by mutations in ABCC9. Am J Hum Genet. 2012;90:1094–101.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Vissers LE, Ligt J de, Gilissen C, et al. A de novo paradigm for mental retardation. Nat Genet. 2010;42:1109–12.

    Article  CAS  PubMed  Google Scholar 

  38. Ligt J de, Willemsen MH, Bon BW van, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012;367: 1921–9.

    Article  PubMed  Google Scholar 

  39. Rauch A, Wieczorek D, Graf E, et al. Range of genetic mutations associated with severe nonsyndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012;380:1674–82.

    Article  CAS  PubMed  Google Scholar 

  40. Najmabadi H, Hu H, Garshasbi M, et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011;478:57–63.

    Article  CAS  PubMed  Google Scholar 

  41. Iqbal Z, Shahzad M, Vissers LE, et al. A compound heterozygous mutation in DPAGT1 results in a congenital disorder of glycosylation with a relatively mild phenotype. Eur J Hum Genet. 2013;21: 844–9.

    Article  CAS  PubMed  Google Scholar 

  42. Murdock DR, Clark GD, Bainbridge MN, et al. Whole-exome sequencing identifies compound heterozygous mutations in WDR62 in siblings with recurrent polymicrogyria. Am J Med Genet A. 2011;155:2071–7.

    Article  CAS  Google Scholar 

  43. Nederlandse Vereniging voor Kindergeneeskunde. Evidence-based richtlijn voor de initiële etiologische diagnostiek bij kinderen met een globale ontwikkelingsachterstand/mentale retardatie. Utrecht: NVK, 2005.

    Google Scholar 

  44. Bamshad MJ, Ng SB, Bigham AW, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011;12:745–55.

    Article  CAS  PubMed  Google Scholar 

  45. Willemsen MH, Vissers LE, Willemsen MA, et al. Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects. J Med Genet. 2012;49:179–83.

    Article  CAS  PubMed  Google Scholar 

  46. Willemsen MH, Nijhof B, Fenckova M, et al. GATAD2B loss-of-function mutations cause a recognisable syndrome with intellectual disability and are associated with learning deficits and synaptic undergrowth in Drosophila. J Med Genet. 2013; 50:507–14.

    Article  CAS  PubMed  Google Scholar 

  47. Poirier K, Lebrun N, Broix L, et al. Mutations in TUBG1, DYNC1H1, KIF5 C and KIF2 A cause malformations of cortical development and microcephaly. Nat Genet. 2013;45:639–47.

    Article  CAS  PubMed  Google Scholar 

  48. Veeramah KR, Johnstone L, Karafet TM, et al. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia. 2013;54:1270–81.

    Article  CAS  PubMed  Google Scholar 

  49. Huisman SA, Redeker EJ, Maas SM, et al. High rate of mosaicism in individuals with Cornelia de Lange syndrome. J Med Genet. 2013;50:339–44.

    Article  CAS  PubMed  Google Scholar 

  50. Biesecker LG, Spinner NB. A genomic view of mosaicism and human disease. Nat Rev Genet. 2013;14:307–20.

    Article  CAS  PubMed  Google Scholar 

  51. Pagnamenta AT, Lise S, Harrison V, et al. Exome sequencing can detect pathogenic mosaic mutations present at low allele frequencies. J Hum Genet. 2012;57:70–2.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. afdeling Genetica, Radboudumc, 836 Klinische Genetica, 9101, 6500, HB, Nijmegen, The Netherlands

    M.H. Willemsen,  T. Kleefstra &  H.G. Yntema

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  1. M.H. Willemsen
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  2. T. Kleefstra
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  3. H.G. Yntema
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Correspondence to M.H. Willemsen.

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Mw. dr. M.H. Willemsen, klinisch geneticus i.o., mw. dr. T. Kleefstra, klinisch geneticus, mw. dr. H.G. Yntema, laboratoriumspecialist klinische genetica, afdeling Genetica, Radboudumc, Nijmegen.

Correspondentieadres: M.H. Willemsen, 836 Klinische Genetica, Radboudumc, Postbus 9101, 6500 HB Nijmegen, marjolein.willemsen@radboudumc.nl.

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Willemsen, M., Kleefstra, T. & Yntema, H. Exoom-sequencing in de diagnostiek van ontwikkelingsachterstand/verstandelijke beperking. TIJDSCHR. KINDERGENEESKUNDE 82, 35–44 (2014). https://doi.org/10.1007/s12456-014-0005-x

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