Long contiguous stretches of homozygosity spanning shortly the imprinted loci are associated with intellectual disability, autism and/or epilepsy

Molecular Cytogenetics

Yuri B. Yurov²  Maria A. Zelenova²  Sergei A. Korostelev³  Svetlana G. Vorsanova²  Ivan Y. Iourov¹ 

[1] Department of Medical Genetics, Russian Medical Academy of Postgraduate Education, Moscow, 123995, Russia;Separated Structural Unit “Clinical Research Institute of Pediatrics”, Russian National Research Medical University named after N.I. Pirogov, Ministry of Health of Russian Federation, Moscow, 125412, Russia;Research Centre for Medical Genetics, Moscow, 115478, Russia

关键词: Bioinformatics;    Epigenetics;    Epilepsy;    Autism;    Intellectual disability, Congenital anomalies;    Long continuous stretches of homozygosity;   

Others  :  1229983
DOI  :  10.1186/s13039-015-0182-z

 received in 2015-08-14, accepted in 2015-09-27,  发布年份 2015

【 摘 要 】

Background

Long contiguous stretches of homozygosity (LCSH) (regions/runs of homozygosity) are repeatedly detected by single-nucleotide polymorphism (SNP) chromosomal microarrays. Providing important clues regarding parental relatedness (consanguinity), uniparental disomy, chromosomal recombination or rearrangements, LCSH are rarely considered as a possible epigenetic cause of neurodevelopmental disorders. Additionally, despite being relevant to imprinting, LCSH at imprinted loci have not been truly addressed in terms of pathogenicity. In this study, we examined LCSH in children with unexplained intellectual disability, autism, congenital malformations and/or epilepsy focusing on chromosomal regions which harbor imprinted disease genes.

Results

Out of 267 cases, 14 (5.2 %) were found to have LCSH at imprinted loci associated with a clinical outcome. There were 5 cases of LCSH at 15p11.2, 4 cases of LCSH at 7q31.2, 3 cases of LCSH at 11p15.5, and 2 cases of LCSH at 7q21.3. Apart from a case of LCSH at 7q31.33q32.3 (~4 Mb in size), all causative LCSH were 1–1.5 Mb in size. Clinically, these cases were characterized by a weak resemblance to corresponding imprinting diseases (i.e., Silver-Russell, Beckwith-Wiedemann, and Prader-Willi/Angelman syndromes), exhibiting distinctive intellectual disability, autistic behavior, developmental delay, seizures and/or facial dysmorphisms. Parental consanguinity was detected in 8 cases (3 %), and these cases did not exhibit LCSH at imprinted loci.

Conclusions

This study demonstrates that shorter LCSH at chromosomes 7q21.3, 7q31.2, 11p15.5, and 15p11.2 occur with a frequency of about 5 % in the children with intellectual disability, autism, congenital malformations and/or epilepsy. Consequently, this type of epigenetic mutations appears to be the most common one among children with neurodevelopmental diseases. Finally, since LCSH less than 2.5–10 Mb in size are generally ignored in diagnostic SNP microarray studies, one can conclude that an important epigenetic cause of intellectual disability, autism or epilepsy is actually overlooked.

【 授权许可】

   
2015 Iourov et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

【 参考文献 】

• [1]Ellison JW, Rosenfeld JA, Shaffer LG. Genetic basis of intellectual disability. Annu Rev Med. 2013; 64:441-450.
• [2]Huguet G, Ey E, Bourgeron T. The genetic landscapes of autism spectrum disorders. Annu Rev Genomics Hum Genet. 2013; 14:191-213.
• [3]Iourov IY, Vorsanova SG, Yurov YB. Molecular cytogenetics and cytogenomics of brain diseases. Curr Genomics. 2008; 9(7):452-465.
• [4]Mefford HC, Batshaw ML, Hoffman EP. Genomics, intellectual disability, and autism. N Engl J Med. 2012; 366(8):733-743.
• [5]Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T et al.. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012; 380(9854):1674-1682.
• [6]Srivastava AK, Schwartz CE. Intellectual disability and autism spectrum disorders: causal genes and molecular mechanisms. Neurosci Biobehav Rev. 2014; 46(Pt 2):161-174.
• [7]Vorsanova SG, Yurov YB, Soloviev IV, Iourov IY. Molecular cytogenetic diagnosis and somatic genome variations. Curr Genomics. 2010; 11(6):440-446.
• [8]Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004; 429(6990):457-463.
• [9]Liehr T. Cytogenetic contribution to uniparental disomy (UPD). Mol Cytogenet. 2010; 3:8. BioMed Central Full Text
• [10]Rangasamy S, D’Mello SR, Narayanan V. Epigenetics, autism spectrum, and neurodevelopmental disorders. Neurotherapeutics. 2013; 10(4):742-756.
• [11]Smith CL, Bolton A, Nguyen G. Genomic and epigenomic instability, fragile sites, schizophrenia and autism. Curr Genomics. 2010; 11(6):447-469.
• [12]Iourov IY, Vorsanova SG, Yurov YB. Single cell genomics of the brain: focus on neuronal diversity and neuropsychiatric diseases. Curr Genomics. 2012; 13(6):477-488.
• [13]Li LH, Ho SF, Chen CH, Wei CY, Wong WC, Li LY et al.. Long contiguous stretches of homozygosity in the human genome. Hum Mutat. 2006; 27(11):1115-1121.
• [14]McQuillan R, Leutenegger AL, Abdel-Rahman R, Franklin CS, Pericic M, Barac-Lauc L et al.. Runs of homozygosity in European populations. Am J Hum Genet. 2008; 83(3):359-372.
• [15]Kirin M, McQuillan R, Franklin CS, Campbell H, McKeigue PM, Wilson JF. Genomic runs of homozygosity record population history and consanguinity. PLoS One. 2010; 5(11): Article ID e13996
• [16]Bruno DL, White SM, Ganesamoorthy D, Burgess T, Butler K, Corrie S et al.. Pathogenic aberrations revealed exclusively by single nucleotide polymorphism (SNP) genotyping data in 5000 samples tested by molecular karyotyping. J Med Genet. 2011; 48(12):831-839.
• [17]Lin PI, Kuo PH, Chen CH, Wu JY, Gau SS, Wu YY et al.. Runs of homozygosity associated with speech delay in autism in a Taiwanese Han population: evidence for the recessive model. PLoS One. 2013; 8(8): Article ID e72056
• [18]D’Amours G, Langlois M, Mathonnet G, Fetni R, Nizard S, Srour M et al.. SNP arrays: comparing diagnostic yields for four platforms in children with developmental delay. BMC Med Genomics. 2014; 7:70. BioMed Central Full Text
• [19]Gandin I, Faletra F, Faletra F, Carella M, Pecile V, Ferrero GB et al.. Excess of runs of homozygosity is associated with severe cognitive impairment in intellectual disability. Genet Med. 2015; 17(5):396-399.
• [20]Grote L, Myers M, Lovell A, Saal H, Lipscomb SK. Variability in laboratory reporting practices for regions of homozygosity indicating parental relatedness as identified by SNP microarray testing. Genet Med. 2012; 14(12):971-976.
• [21]Wang JC, Ross L, Mahon LW, Owen R, Hemmat M, Wang BT et al.. Regions of homozygosity identified by oligonucleotide SNP arrays: evaluating the incidence and clinical utility. Eur J Hum Genet. 2015; 23(5):663-671.
• [22]Ku CS, Naidoo N, Teo SM, Pawitan Y. Regions of homozygosity and their impact on complex diseases and traits. Hum Genet. 2011; 129(1):1-15.
• [23]Szpiech ZA, Xu J, Pemberton TJ, Peng W, Zöllner S, Rosenberg NA et al.. Long runs of homozygosity are enriched for deleterious variation. Am J Hum Genet. 2013; 93(1):90-102.
• [24]Fagiolini M, Jensen CL, Champagne FA. Epigenetic influences on brain development and plasticity. Curr Opin Neurobiol. 2009; 19(2):207-212.
• [25]Iourov IY, Vorsanova SG, Yurov YB. Somatic cell genomics of brain disorders: a new opportunity to clarify genetic-environmental interactions. Cytogenet Genome Res. 2013; 139(3):181-188.
• [26]Heron EA, Cormican P, Donohoe G, O’Neill FA, Kendler KS, Riley BP et al.. No evidence that runs of homozygosity are associated with schizophrenia in an Irish genome-wide association dataset. Schizophr Res. 2014; 154(1–3):79-82.
• [27]Melhem NM, Lu C, Dresbold C, Middleton FA, Klei L, Wood S et al.. Characterizing runs of homozygosity and their impact on risk for psychosis in a population isolate. Am J Med Genet B Neuropsychiatr Genet. 2014; 165B(6):521-530.
• [28]Power RA, Keller MC, Ripke S, Abdellaoui A, Wray NR, Sullivan PF et al.. A recessive genetic model and runs of homozygosity in major depressive disorder. Am J Med Genet B Neuropsychiatr Genet. 2014; 165B(2):157-166.
• [29]Gamsiz ED, Viscidi EW, Frederick AM, Nagpal S, Sanders SJ, Murtha MT et al.. Intellectual disability is associated with increased runs of homozygosity in simplex autism. Am J Hum Genet. 2013; 93(1):103-109.
• [30]Kalish JM, Jiang C, Bartolomei MS. Epigenetics and imprinting in human disease. Int J Dev Biol. 2014; 58(2–4):291-298.
• [31]Peters J. The role of genomic imprinting in biology and disease: an expanding view. Nat Rev Genet. 2014; 15(8):517-530.
• [32]Fan YS, Ouyang X, Peng J, Sacharow S, Tekin M, Barbouth D, et al. Frequent detection of parental consanguinity in children with developmental disorders by a combined CGH and SNP microarray. Mol Cytogenet. 2013;6.
• [33]McCann JA, Zheng H, Islam A, Goodyer CG, Polychronakos C. Evidence against GRB10 as the gene responsible for Silver-Russell syndrome. Biochem Biophys Res Commun. 2001; 286(5):943-948.
• [34]Bartholdi D, Krajewska-Walasek M, Ounap K, Gaspar H, Chrzanowska KH, Ilyana H et al.. Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS): results from a large cohort of patients with SRS and SRS-like phenotypes. J Med Genet. 2009; 46(3):192-197.
• [35]Begemann M, Spengler S, Gogiel M, Grasshoff U, Bonin M, Betz RC et al.. Clinical significance of copy number variations in the 11p15.5 imprinting control regions: new cases and review of the literature. J Med Genet. 2012; 49(9):547-553.
• [36]Mussa A, Russo S, Larizza L, Riccio A, Ferrero GB. (Epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome: a paradigm for genomic medicine. Clin Genet. 2015.
• [37]Horsthemke B. Mechanisms of imprint dysregulation. Am J Med Genet C: Semin Med Genet. 2010; 154C(3):321-328.
• [38]Iourov IY, Vorsanova SG, Yurov YB. Chromosomal variation in mammalian neuronal cells: known facts and attractive hypotheses. Int Rev Cytol. 2006; 249:143-191.
• [39]Iourov IY, Vorsanova SG, Yurov YB. Chromosomal mosaicism goes global. Mol Cytogenet. 2008; 1:26. BioMed Central Full Text
• [40]Satterlee JS, Beckel-Mitchener A, Little R, Procaccini D, Rutter JL, Lossie AC. Neuroepigenomics: Resources, Obstacles, and Opportunities. Neuroepigenetics. 2015; 1:2-13.
• [41]Iourov IY, Vorsanova SG, Yurov YB. Recent patents on molecular cytogenetics. Recent Pat DNA Gene Seq. 2008; 2(1):6-15.
• [42]Kearney HM, Kearney JB, Conlin LK. Diagnostic implications of excessive homozygosity detected by SNP-based microarrays: consanguinity, uniparental disomy, and recessive single-gene mutations. Clin Lab Med. 2011; 31(4):595-613.
• [43]Kalsner L, Chamberlain SJ. Prader-Willi, Angelman, and 15q11-q13 Duplication Syndromes. Pediatr Clin North Am. 2015; 62(3):587-606.
• [44]Margolis SS, Sell GL, Zbinden MA, Bird LM. Angelman Syndrome. Neurotherapeutics. 2015; 12(3):641-650.
• [45]Curtis D. Extended homozygosity is not usually due to cytogenetic abnormality. BMC Genet. 2007; 8:67. BioMed Central Full Text
• [46]Iourov IY, Vorsanova SG, Yurov YB. In silico molecular cytogenetics: a bioinformatic approach to prioritization of candidate genes and copy number variations for basic and clinical genome research. Mol Cytogenet. 2014; 7:98. BioMed Central Full Text
• [47]Cui H, Dhroso A, Johnson N, Korkin D. The variation game: Cracking complex genetic disorders with NGS and omics data. Methods. 2015; 79–80:18-31.
• [48]Iourov IY, Vorsanova SG, Kurinnaaya OS, Kolotii AD, Demidova IA, Kravets VS et al.. The use of molecular cytogenetic and cytogenetic techniques for the diagnosis of Prader-Willi and Angelman syndrome. Zh Nevrol Psikhiatr Im S S Korsakova. 2014; 114(1):49-53.
• [49]Vorsanova SG, Yurov IY, Demidova IA, Voinova-Ulas VY, Kravets VS, Solov’ev IV et al.. 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(6):553-558.
• [50]Yurov YB, Vorsanova SG, Iourov IY, Demidova IA, Beresheva AK, Kravetz VS et al.. Unexplained autism is frequently associated with low-level mosaic aneuploidy. J Med Genet. 2007; 44(8):521-525.
• [51]Iourov IY, Vorsanova SG, Kurinnaia OS, Zelenova MA, Silvanovich AP, Yurov YB. Molecular karyotyping by array CGH in a Russian cohort of children with intellectual disability, autism, epilepsy and congenital anomalies. Mol Cytogenet. 2012; 5:46. BioMed Central Full Text
• [52]Iourov IY, Vorsanova SG, Voinova VY, Kurinnaia OS, Zelenova MA, Demidova IA et al.. Xq28 (MECP2) microdeletions are common in mutation-negative females with Rett syndrome and cause mild subtypes of the disease. Mol Cytogenet. 2013; 6:53. BioMed Central Full Text
• [53]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(14):2656-2669.