Molecular karyotyping by array CGH in a Russian cohort of children with intellectual disability, autism, epilepsy and congenital anomalies

Molecular Cytogenetics

Yuri B Yurov¹  Alexandra P Silvanovich³  Maria A Zelenova¹  Oxana S Kurinnaia¹  Svetlana G Vorsanova¹  Ivan Y Iourov² 

[1] Moscow City University of Psychology and Education, Moscow, Russia;Institute of Pediatrics and Children Surgery, Ministry of Health of the Russian Federation, 125412, Moscow, Russia;Mental Health Research Center, Russian Academy of Medical Sciences, 119152, Moscow, Russia

关键词: Copy number viriations (CNVs);    Chromosome abnormalities;    Chromosome imbalances;    Genome variations;    Epilepsy;    Autism;    Congenital anomalies;    Intellectual disability;    Array CGH;   

Others  :  1151183
DOI  :  10.1186/1755-8166-5-46

 received in 2012-12-13, accepted in 2012-12-14,  发布年份 2012

【 摘 要 】

Background

Array comparative genomic hybridization (CGH) has been repeatedly shown to be a successful tool for the identification of genomic variations in a clinical population. During the last decade, the implementation of array CGH has resulted in the identification of new causative submicroscopic chromosome imbalances and copy number variations (CNVs) in neuropsychiatric (neurobehavioral) diseases. Currently, array-CGH-based technologies have become an integral part of molecular diagnosis and research in individuals with neuropsychiatric disorders and children with intellectual disability (mental retardation) and congenital anomalies. Here, we introduce the Russian cohort of children with intellectual disability, autism, epilepsy and congenital anomalies analyzed by BAC array CGH and a novel bioinformatic strategy.

Results

Among 54 individuals highly selected according to clinical criteria and molecular and cytogenetic data (from 2426 patients evaluated cytogenetically and molecularly between November 2007 and May 2012), chromosomal imbalances were detected in 26 individuals (48%). In two patients (4%), a previously undescribed condition was observed. The latter has been designated as meiotic (constitutional) genomic instability resulted in multiple submicroscopic rearrangements (including CNVs). Using bioinformatic strategy, we were able to identify clinically relevant CNVs in 15 individuals (28%). Selected cases were confirmed by molecular cytogenetic and molecular genetic methods. Eight out of 26 chromosomal imbalances (31%) have not been previously reported. Among them, three cases were co-occurrence of subtle chromosome 9 and 21 deletions.

Conclusions

We conducted an array CGH study of Russian patients suffering from intellectual disability, autism, epilepsy and congenital anomalies. In total, phenotypic manifestations of clinically relevant genomic variations were found to result from genomic rearrangements affecting 1247 disease-causing and pathway-involved genes. Obviously, a significantly lesser part of them are true candidates for intellectual disability, autism or epilepsy. The success of our preliminary array CGH and bioinformatic study allows us to expand the cohort. According to the available literature, this is the first comprehensive array CGH evaluation of a Russian cohort of children with neuropsychiatric disorders and congenital anomalies.

【 授权许可】

   
2012 Iourov et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Bejjani BA, Shaffer LG: Application of array-based comparative genomic hybridization to clinical diagnostics. J Mol Diagn 2006, 8:528-533.
• [2]Knight SJ, Regan R: Idiopathic learning disability and genome imbalance. Cytogenet Genome Res 2006, 115:215-224.
• [3]Emanuel BS, Saitta SC: From microscopes to microarrays: dissecting recurrent chromosomal rearrangements. Nat Rev Genet 2007, 8:869-883.
• [4]Stankiewicz P, Beaudet AL: Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr Opin Genet Dev 2007, 17:182-192.
• [5]Lee C, Iafrate AJ, Brothman AR: Copy number variations and clinical cytogenetic diagnosis of constitutional disorders. Nat Genet 2007, 39(7 Suppl):S48-S54.
• [6]Bejjani BA, Shaffer LG: Clinical utility of contemporary molecular cytogenetics. Annu Rev Genomics Hum Genet 2008, 9:71-86.
• [7]Iourov IY, Vorsanova SG, Yurov YB: Molecular cytogenetics and cytogenomics of brain diseases. Curr Genomics 2008, 9:452-465.
• [8]Sagoo GS, Butterworth AS, Sanderson S, Shaw-Smith C, Higgins JP, Burton H: 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, 11:139-146.
• [9]Vissers LE, de Vries BB, Veltman JA: Genomic microarrays in mental retardation: from copy number variation to gene, from research to diagnosis. J Med Genet 2010, 47:289-297.
• [10]Hochstenbach R, Buizer-Voskamp JE, Vorstman JA, Ophoff RA: Genome arrays for the detection of copy number variations in idiopathic mental retardation, idiopathic generalized epilepsy and neuropsychiatric disorders: lessons for diagnostic workflow and research. Cytogenet Genome Res 2011, 135:174-202.
• [11]ISCN: An International System of Human Cytogenetic Nomenclature, Shaffer LG, McGowan-Jordan J, Schmid M (eds); S. Basel: Karger; 2013. 2013
• [12]Slavotinek AM: Novel microdeletion syndromes detected by chromosome microarrays. Hum Genet 2008, 124:1-17.
• [13]Gersen SL, Keagle MB: The principles of clinical cytogenetics. Humana press 2005.
• [14]Iourov IY, Vorsanova SG, Yurov YB: Chromosomal variation in mammalian neuronal cells: known facts and attractive hypotheses. Int Rev Cytol 2006, 249:143-191.
• [15]Reddy KS: Double trisomy in spontaneous abortions. Hum Genet 1997, 101:339-345.
• [16]Vorsanova SG, Iourov IY, Demidova IA, Kirillova EA, Soloviev IV, Yurov YB: Chimerism and multiple numerical chromosome imbalances in a spontaneously aborted fetus. Tsitol Genet 2006, 40:28-30.
• [17]Malan V, Raoul O, Firth HV, Royer G, Turleau C, Bernheim A, Willatt L, Munnich A, Vekemans M, Lyonnet S, Cormier-Daire V, Colleaux L: 19q13.11 deletion syndrome: a novel clinically recognisable genetic condition identified by array comparative genomic hybridisation. J Med Genet 2009, 46:635-640.
• [18]Hiraki Y, Nishimura A, Hayashidani M, Terada Y, Nishimura G, Okamoto N, Nishina S, Tsurusaki Y, Doi H, Saitsu H, Miyake N, Matsumoto N: A de novo deletion of 20q11.2-q12 in a boy presenting with abnormal hands and feet, retinal dysplasia, and intractable feeding difficulty. Am J Med Genet A 2011, 155A:409-414.
• [19]Hansson KB, Gijsbers AC, Oostdijk W, Rehbock JJ, de Snoo F, Ruivenkamp CA, Kant SG: Molecular and clinical characterization of patients with a ring chromosome 11. Eur J Med Genet 2012, 55:708-714.
• [20]Zollino M, Murdolo M, Marangi G, Pecile V, Galasso C, Mazzanti L, Neri G: On the nosology and pathogenesis of Wolf-Hirschhorn syndrome: genotype-phenotype correlation analysis of 80 patients and literature review. Am J Med Genet C Semin Med Genet 2008, 148C:257-269.
• [21]Donnenfeld AE, Graham JM Jr, Packer RJ, Aquino R, Berg SZ, Emanuel BS: Microphthalmia and chorioretinal lesions in a girl with an Xp22.2-pter deletion and partial 3p trisomy: clinical observations relevant to Aicardi syndrome gene localization. Am J Med Genet 1990, 37:182-186.
• [22]Han DH, Chang JY, Lee WI, Bae CW: A case of partial trisomy 3p syndrome with rare clinical manifestations. Korean J Pediatr 2012, 55:107-110.
• [23]Rehnström K, Ylisaukko-oja T, Nieminen-von Wendt T, Sarenius S, Källman T, Kempas E, von Wendt L, Peltonen L, Järvelä I: Independent replication and initial fine mapping of 3p21-24 in Asperger syndrome. J Med Genet 2006, 43:6.
• [24]Alesi V, Bertoli M, Barrano G, Torres B, Pusceddu S, Pastorino M, Perria C, Nardone AM, Novelli A, Serra G: 335.4 kb microduplication in chromosome band Xp11.2p11.3 associated with developmental delay, growth retardation, autistic disorder and dysmorphic features. Gene 2012, 505:384-387.
• [25]Siggberg L, Olsén P, Näntö-Salonen K, Knuutila S: 19p13.3 aberrations are associated with dysmorphic features and deviant psychomotor development. Cytogenet Genome Res 2011, 132:8-15.
• [26]El-Hattab AW, Fang P, Jin W, Hughes JR, Gibson JB, Patel GS, Grange DK, Manwaring LP, Patel A, Stankiewicz P, Cheung SW: Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions. J Med Genet 2011, 48:840-850.
• [27]Vorsanova SG, Iourov IY, Voinova-Ulas VY, Weise A, Monakhov VV, Kolotii AD, Soloviev IV, Novikov PV, Yurov YB, Liehr T: Partial monosomy 7q34-qter and 21pter-q22.13 due to cryptic unbalanced translocation t(7;21) but not monosomy of the whole chromosome 21: a case report plus review of the literature. Mol Cytogenet 2008, 1:13. BioMed Central Full Text
• [28]Park JH, Woo JH, Shim SH, Yang SJ, Choi YM, Yang KS, Cha DH: Application of a target array comparative genomic hybridization to prenatal diagnosis. BMC Med Genet 2010, 11:102.
• [29]Vorsanova SG, Demidova IA, Ulas VY, Soloviev IV, Kazantzeva LZ, Yurov YB: Cytogenetic and molecular-cytogenetic investigation of Rett syndrome: analysis of 31 cases. Neuroreport 1996, 8:187-189.
• [30]Vorsanova SG, Yurov YB, Ulas VY, Demidova IA, Sharonin VO, Kolotii AD, Gorbatchevskaia NL, Beresheva AK, Soloviev IV: Cytogenetic and molecular-cytogenetic studies of Rett syndrome (RTT): a retrospective analysis of a Russian cohort of RTT patients (the investigation of 57 girls and three boys). Brain Dev 2001, 23(Suppl 1):S196-S201.
• [31]Vorsanova SG, Iourov IY, Yurov YB: Neurological, genetic and epigenetic features of Rett syndrome. J Pediatr Neurol 2004, 2:179-190.
• [32]Mitter D, Ullmann R, Muradyan A, Klein-Hitpass L, Kanber D, Ounap K, Kaulisch M, Lohmann D: Genotype-phenotype correlations in patients with retinoblastoma and interstitial 13q deletions. Eur J Hum Genet. 2011, 19:947-958.
• [33]Giannandrea M, Bianchi V, Mignogna ML, Sirri A, Carrabino S, D'Elia E, Vecellio M, Russo S, Cogliati F, Larizza L, et al.: Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly. Am J Hum Genet 2010, 86:185-195.
• [34]Sommer A, Pastore M, Wenger G: Trisomy 16p: a longitudinal profile and photo essay. Am J Med Genet A 2006, 140:174-179.
• [35]Shimojima K, Okamoto N, Suzuki Y, Saito M, Mori M, Yamagata T, Momoi MY, Hattori H, Okano Y, Hisata K, et al.: Subtelomeric deletions of 1q43q44 and severe brain impairment associated with delayed myelination. J Hum Genet 2012, 57:593-600.
• [36]Vorsanova SG, Yurov YB, Iourov IY: Human interphase chromosomes: a review of available molecular cytogenetic technologies. Mol Cytogenet 2010, 3:1. BioMed Central Full Text
• [37]Iourov IY, Vorsanova SG, Yurov YB: Chromosomal mosaicism goes global. Mol Cytogenet 2008, 1:26. BioMed Central Full Text
• [38]Iourov IY: Vorsanova SG. Yurov YB: Somatic Genome Variations. eLS; 2012.
• [39]Iourov IY, Vorsanova SG, Yurov YB: Intercellular genomic (chromosomal) variations resulting in somatic mosaicism: mechanisms and consequences. Curr Genomics 2006, 7:435-446.
• [40]Iourov IY, Vorsanova SG, Yurov YB: Somatic genome variations in health and disease. Curr Genomics 2010, 11:387-396.
• [41]Vorsanova SG, Yurov YB, Soloviev IV, Iourov IY: Molecular cytogenetic diagnosis and somatic genome variations. Curr Genomics 2010, 11:440-446.
• [42]Vorsanova S, Yurov IY, Demidova I, Voinova-Ulas VY, Kravets V, Solov’ev I, Gorbachevskaya NL, Yurov YB: Variability in the heterochromatin regions of the chromosomes and chromosomal anomalies in children with autism: identification of genetic markers of autistic spectrum disorders. Neurosci Behav Physiol 2007, 37:553-558.
• [43]Yurov YB, Vorsanova SG, Iourov IY, Demidova IA, Beresheva AK, Kravetz VS, Monakhov VV, Kolotii AD, Voinova-Ulas VY, Gorbachevskaya NL: Unexplained autism is frequently associated with low-level mosaic aneuploidy. J Med Genet 2007, 44:521-525.
• [44]Vorsanova SG, Voinova VY, Yurov IY, Kurinnaya OS, Demidova IA, Yurov YB: Cytogenetic, molecular-cytogenetic, and clinical-genealogical studies of the mothers of children with autism: a search for familial genetic markers for autistic disorders. Neurosci Behav Physiol 2010, 40:745-756.
• [45]Vorsanova S, Koloti D, Sharonin V, Soloviev V, Yurov Y: FISH analysis of microaberrations at telomeric and subtelomeric regions in chromosomes of children with mental retardation. Am J Hum Genet 1998, 63(suppl 4):A154-A873.
• [46]Caserta D, Benkhalifa M, Baldi M, Fiorentino F, Qumsiyeh M, Moscarini M: Genome profiling of ovarian adenocarcinomas using pangenomic BACs microarray comparative genomic hybridization. Mol Cytogenet 2008, 1:10. BioMed Central Full Text
• [47]Yurov YB, Soloviev IV, Vorsanova SG, Marcais B, Roizes G, Lewis R: High resolution multicolor fluorescence in situ hybridization using cyanine and fluorescein dyes: rapid chromosome identification by directly fluorescently labeled alphoid DNA probes. Hum Genet 1996, 97:390-398.
• [48]Yurov Y, Vorsanova S, Soloviev I, Demidova I, Alexandrov I, Sharonin V, Beresheva A: Original collection of DNA probes for preimplanta tional, fetal prenatal and postnatal diagnosis of chromosomal analysis by FISH. Early prenatal diagnosis, fetal cells and DNA in mother, present state and per spectives/Eds M Macek, D Bianchi, H Cuckle–Prague 2002, 275-283.
• [49]Iourov IY, Vorsanova SG, Liehr T, Kolotii AD, Yurov YB: Increased chromosome instability dramatically disrupts neural genome integrity and mediates cerebellar degeneration in the ataxia-telangiectasia brain. Hum Mol Genet 2009, 18:2656-2669.
• [50]Iourov IY, Vorsanova SG, Saprina EA, Yurov YB: Identification of candidate genes of autism on the basis of molecular cytogenetic and in silico studies of the genome organization of chromosomal regions involved in unbalanced rearrangements. Russ J Genet 2010, 46:1190-1193.