2658-6533Research Results in Biomedicine2658-653310.18413/2658-6533-2023-9-3-0-23162Genetics<strong>Outcomes of ROHs (runs of homozygosity)/LCSHs (long contiguous stretches of homozygosity) spanning the imprinted loci of chromosomes 7, 11 and 15 among children with neurodevelopmental disorders</strong><strong>Outcomes of ROHs (runs of homozygosity)/LCSHs (long contiguous stretches of homozygosity) spanning the imprinted loci of chromosomes 7, 11 and 15 among children with neurodevelopmental disorders</strong>KurinnaiaOksana S.KurinnaiaOksana S.kurinnaiaos@mail.ruVasinKirill S.VasinKirill S.vasin-ks@rambler.ruZelenovaMaria A.ZelenovaMaria A.maria_zelenova@yahoo.comYurovYuri B.YurovYuri B.ivan.iourov@gmail.comVoinovaVictoria Y.VoinovaVictoria Y.vivoinova@yandex.ruVorsanovaSvetlana G.VorsanovaSvetlana G.svorsanova@mail.ruIourovIvan Y.IourovIvan Y.ivan.iourov@gmail.com20239300

Background:&nbsp;Runs of homozygosity or long contiguous stretches of homozygosity (ROHs/LCSHs) are common in the human genome. ROHs/LCSHs spanning the imprinted loci have been previously associated with neurodevelopmental disorders. However, the outcomes of these epigenomic variations remain enigmatic. Accordingly, there is a need to evaluate the ROHs/LCSHs outcomes covering the imprinted loci. The aim of the study:&nbsp;To describe the outcomes of ROHs/LCSHs spanning the imprinted loci of chromosomes 7, 11 and 15 among children with neurodevelopmental disorders. Materials and methods:&nbsp;Using molecular karyotyping by high-resolution SNP array, we obtained data on ROHs/LCSHs from 772 children with neurodevelopmental disorders and congenital malformations. ROHs/LCSHs spanning the imprinted loci of chromosomes 7, 11 and 15 were additionally analyzed by original bioinformatic approaches to uncover the pathogenic value. Results:&nbsp;ROHs/LCSHs spanning the imprinted loci of chromosomes 7, 11 and 15 were detected in 67 (8.7%) individuals. Bioinformatic analyses demonstrated that ROHs/LCSHs affecting imprinted loci of chromosome 7 are not associated with clearly recognizable outcomes. Alternatively, ROHs/LCSHs affecting imprinted loci of chromosome 11 (11p15.5p15.4; Beckwith-Wiedemann syndrome) and chromosome 15 (15q11.2; Prader-Willi/Angelman syndromes) were associated with distinct outcomes as shown by bioinformatics approaches. Prader-Willi/Angelman syndrome loci were affected in 18 cases (2.3%), whereas Beckwith-Wiedemann syndrome loci were affected in 10 cases (1.3%). Conclusion:&nbsp;Analysis of the outcomes of ROHs/LCSHs spanning the imprinted loci of chromosomes 7, 11 and 15 has demonstrated that the epigenomic changes affecting 11p15.5p15.4, and 15q11.2 (28 cases; 3.6%) are associated with atypical forms of Beckwith-Wiedemann and Prader-Willi/Angelman syndromes, respectively. The outcomesof ROHs/LCSHs in chromosome 7 have not been found convincing for a definitive conclusion about the phenotypic effects. Molecular karyotyping by SNP array is a valuable diagnostic technique offering opportunities for detecting these common but underestimated epigenetic causes for neurodevelopmental disorders and congenital malformations.

Background:&nbsp;Runs of homozygosity or long contiguous stretches of homozygosity (ROHs/LCSHs) are common in the human genome. ROHs/LCSHs spanning the imprinted loci have been previously associated with neurodevelopmental disorders. However, the outcomes of these epigenomic variations remain enigmatic. Accordingly, there is a need to evaluate the ROHs/LCSHs outcomes covering the imprinted loci. The aim of the study:&nbsp;To describe the outcomes of ROHs/LCSHs spanning the imprinted loci of chromosomes 7, 11 and 15 among children with neurodevelopmental disorders. Materials and methods:&nbsp;Using molecular karyotyping by high-resolution SNP array, we obtained data on ROHs/LCSHs from 772 children with neurodevelopmental disorders and congenital malformations. ROHs/LCSHs spanning the imprinted loci of chromosomes 7, 11 and 15 were additionally analyzed by original bioinformatic approaches to uncover the pathogenic value. Results:&nbsp;ROHs/LCSHs spanning the imprinted loci of chromosomes 7, 11 and 15 were detected in 67 (8.7%) individuals. Bioinformatic analyses demonstrated that ROHs/LCSHs affecting imprinted loci of chromosome 7 are not associated with clearly recognizable outcomes. Alternatively, ROHs/LCSHs affecting imprinted loci of chromosome 11 (11p15.5p15.4; Beckwith-Wiedemann syndrome) and chromosome 15 (15q11.2; Prader-Willi/Angelman syndromes) were associated with distinct outcomes as shown by bioinformatics approaches. Prader-Willi/Angelman syndrome loci were affected in 18 cases (2.3%), whereas Beckwith-Wiedemann syndrome loci were affected in 10 cases (1.3%). Conclusion:&nbsp;Analysis of the outcomes of ROHs/LCSHs spanning the imprinted loci of chromosomes 7, 11 and 15 has demonstrated that the epigenomic changes affecting 11p15.5p15.4, and 15q11.2 (28 cases; 3.6%) are associated with atypical forms of Beckwith-Wiedemann and Prader-Willi/Angelman syndromes, respectively. The outcomesof ROHs/LCSHs in chromosome 7 have not been found convincing for a definitive conclusion about the phenotypic effects. Molecular karyotyping by SNP array is a valuable diagnostic technique offering opportunities for detecting these common but underestimated epigenetic causes for neurodevelopmental disorders and congenital malformations.

chromosomeruns of homozygositylong contiguous stretches of homozygosityneurodevelopmental disordersSNP arraybioinformaticscytogenomicschromosomeruns of homozygositylong contiguous stretches of homozygosityneurodevelopmental disordersSNP arraybioinformaticscytogenomicsСписок литературыCeballos FC, Joshi PK, Clark DW, et al. Runs of homozygosity: windows into population history and trait architecture. Nature Reviews Genetics. 2018;19(4):220-234. DOI: https://doi.org/10.1038/nrg.2017.109Szpiech ZA, Mak ACY, White MJ, et al. Ancestry-dependent enrichment of deleterious homozygotes in runs of homozygosity. American Journal of Human Genetics. 2019;105(4):747-762. DOI: https://10.1016/j.ajhg.2019.08.011Iourov IY, Vorsanova SG, Korostelev SA, et al. Long contiguous stretches of homozygosity spanning shortly the imprinted loci are associated with intellectual disability, autism and/or epilepsy. Molecular Cytogenetics. 2015;8:77. DOI: https://doi.org/10.1186/s13039-015-0199-3Iourov IY, Vorsanova SG, Zelenova MA, et al. Epigenomic variations manifesting as a loss of heterozygosity affecting imprinted genes represent a molecular mechanism of autism spectrum disorders and intellectual disability in children. Journal of Neurology i Psychiatry imeni S.S. Korsakova. 2019;119(5):91-97. Russian. DOI: https://doi.org/10.17116/jnevro201911905191Chaves TF, Oliveira LF, Ocampos M, et al. Long contiguous stretches of homozygosity detected by chromosomal microarrays (CMA) in patients with neurodevelopmental disorders in the South of Brazil. BMC Medical Genomics. 2019;12(1):50. DOI: https://10.1186/s12920-019-0496-5Mishra A, Prabha PK, Singla R, et al. Epigenetic interface of autism spectrum disorders (ASDs): implications of chromosome 15q11-q13 segment. ACS Chemical Neuroscience. 2022;13(12):1684-1696. DOI: https://10.1021/acschemneuro.2c00060Iourov IY, Vorsanova SG, Yurov YB. Runs of homozygosity and epigenetic deregulation of genomic imprinting. OBM Genetics 2018;2(3):028. DOI: https://doi.org/10.21926/obm.genet.1803028Iourov IY, Vorsanova SG, Yurov YB. Pathway-based classification of genetic diseases. Molecular Cytogenetics. 2019;12:4. DOI: https://doi.org/10.1186/s13039-019-0418-4Ghulam A, Lei X, Guo M, Bian C. Comprehensive analysis of features and annotations of pathway databases. Current Bioinformatics. 2020;15(8):803-820. DOI: https://doi.org/10.2174/1574893615999200413123352Jiang X-F, Xiong L, Bai L, et al. Structure and dynamics of human complication-disease network. Chaos, Solitons and Fractals. 2022;164:112633. DOI: https://doi.org/10.1016/j.chaos.2022.112633Heng HH, Horne SD, Chaudhry S, et al. A postgenomic perspective on molecular cytogenetics. Current Genomics. 2018;19(3):227-239. DOI: https://doi.org/10.2174/1389202918666170717145716Iourov IY, Vorsanova SG, Yurov YB. The variome concept: focus on CNVariome. Molecular Cytogenetics. 2019;12:52. DOI: https://doi.org/10.1186/s13039-019-0467-8Monk D, Mackay DJG, Eggermann T, et al. Genomic imprinting disorders: lessons on how genome, epigenome and environment interact. Nature Reviews in Genetics. 2019;20(4):235-248. DOI: https://doi.org/10.1038/s41576-018-0092-0Butler MG. Imprinting disorders in humans: a review. Current Opinion in Pediatrics. 2020;32(6):719-729. DOI: https://doi.org/10.1097/MOP.0000000000000965Eggermann T, Davies JH, Tauber M, et al. Growth restriction and genomic imprinting-overlapping phenotypes support the concept of an imprinting network. Genes. 2021;12(4):585. DOI: https://doi.org/10.3390/genes12040585Isles AR. The contribution of imprinted genes to neurodevelopmental and neuropsychiatric disorders. Translational Psychiatry. 2022;12(1):210. DOI: https://doi.org/10.1038/s41398-022-01972-4Aypar U, Hoppman NL, Thorland EC, Dawson DB. Patients with mosaic methylation patterns of the Prader-Willi/Angelman Syndrome critical region exhibit AS-like phenotypes with some PWS features. Molecular Cytogenetics. 2016;9:26. DOI: https://doi.org/10.1186/s13039-016-0233-0Nakabayashi K, Fernandez BA, Teshima I, et al. Molecular genetic studies of human chromosome 7 in Russell-Silver syndrome. Genomics. 2002;79(2):186-96. DOI: https://doi.org/10.1006/geno.2002.6695Sazhenova EA, Lebedev IN. Epigenetic mosaicism in genomic imprinting disorders. Russian Journal of Genetics. 2019;55(10):1196-1207. DOI: https://doi.org/10.1134/S1022795419100119Mendiola AJP, LaSalle JM. Epigenetics in Prader-Willi syndrome. Frontiers in Genetics. 2021;12:624581. DOI: https://doi.org/10.3389/fgene.2021.624581Iourov IY, Vorsanova SG, Yurov YB, et al. The cytogenomic &quot;theory of everything&quot;: chromohelkosis may underlie chromosomal instability and mosaicism in disease and aging. International Journal of Molecular Sciences. 2020;21(21):8328. DOI: https://doi.org/10.3390/ijms21218328Vorsanova SG, Demidova IA, Kolotii AD, et al. Klinefelter syndrome mosaicism in boys with neurodevelopmental disorders: a cohort study and an extension of the hypothesis. Molecular Cytogenetics. 2022;15(1):8. DOI: https://doi.org/10.1186/s13039-022-00588-zRomdhane L, Mezzi N, Dallali H, et al. A map of copy number variations in the Tunisian population: a valuable tool for medical genomics in North Africa. NPJ Genomic Medicine. 2021;6(1):3. DOI: https://doi.org/10.1038/s41525-020-00166-5Iourov IY, Vorsanova SG, Yurov YB. In silico molecular cytogenetics: a bioinformatics approach to prioritization of candidate genes and copy number variations for basic and clinical genome research. Molecular Cytogenetics. 2014;7(1):98. DOI: https://doi.org/10.1186/s13039-014-0098-zYurov YB, Vorsanova SG, Iourov IY. Network-based classification of molecular cytogenetic data. Current Bioinformatics. 2017;12:27-33. DOI: https://doi.org/10.2174/1574893611666160606165119Fan YS, Ouyang X, Peng J, et al. Frequent detection of parental consanguinity in children with developmental disorders by a combined CGH and SNP microarray. Molecular Cytogenetics. 2013;6(1):38. DOI: https://doi.org/10.1186/1755-8166-6-38Del Gaudio D, Shinawi M, Astbury C, et al. ACMG Laboratory Quality Assurance Committee. Diagnostic testing for uniparental disomy: a points to consider statement from the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine. 2020;22(7):1133-1141. DOI: https://doi.org/10.1038/s41436-020-0782-9Vorsanova SG, Yurov YB, Soloviev IV, et al. Molecular cytogenetic diagnosis and somatic genome variations. Current Genomics. 2010;11(6):440-446. DOI: https://doi.org/10.2174/138920210793176010Pellikaan K, van Woerden GM, Kleinendorst L, et al. The diagnostic journey of a patient with Prader-Willi-Like syndrome and a unique homozygous SNURF-SNRPN variant; bio-molecular analysis and review of the literature. Genes. 2021;12(6):875. DOI: https://doi.org/10.3390/genes12060875Iourov IY, Vorsanova SG, Kurinnaaya OS, et al. The use of molecular cytogenetic and cytogenetic techniques for the diagnosis of Prader-Willi and Angelman syndrome. Journal of Neurology i Psychiatry imeni S.S. Korsakova. 2014;114(1):49-53. Russian.Fontana L, Tabano S, Maitz S, et al. Clinical and molecular diagnosis of Beckwith-Wiedemann syndrome with single- or multi-locus imprinting disturbance. International Journal of Molecular Sciences. 2021;22(7):3445. DOI: https://doi.org/10.3390/ijms22073445Andergassen D, Smith ZD, Kretzmer H, et al. Diverse epigenetic mechanisms maintain parental imprints within the embryonic and extraembryonic lineages. Developmental Cell. 2021;56(21):2995-3005.e4. DOI: https://doi.org/10.1016/j.devcel.2021.10.010Jima DD, Skaar DA, Planchart A, et al. Genomic map of candidate human imprint control regions: the imprintome. Epigenetics. 2022;17(13):1920-1943. DOI: https://doi.org/10.1080/15592294.2022.2091815Liehr T. Uniparental disomy is a chromosomic disorder in the first place. Molecular Cytogenetics. 2022;15(1):5. DOI: https://doi.org/10.1186/s13039-022-00585-2Iourov IY, Gerasimov AP, Zelenova MA, et al. Cytogenomic epileptology. Molecular Cytogenetics. 2023;16(1):1. DOI: https://doi.org/10.1186/s13039-022-00634-wHeng E, Thanedar S, Heng HH. Challenges and opportunities for clinical cytogenetics in the 21st century. Genes. 2023;14(2):493. DOI: https://doi.org/10.3390/genes14020493Iourov IY, Vorsanova SG, Yurov YB. Systems cytogenomics: are we ready yet? Current Genomics. 2021;22(2):75-78. DOI: https://doi.org/10.2174/1389202922666210219112419