Russian Journal of GeneticsRussian Journal of GeneticsГенетика0016-67583034-5103The Russian Academy of Sciences66725910.31857/S0016675824050026CJRONRОБЗОРНЫЕ И ТЕОРЕТИЧЕСКИЕ СТАТЬИResearch ArticleCNVs in Patients with Neurodevelopmental Disorders: Meta-AnalysisCNV у пациентов с нарушениями психомоторного развития: метаанализFedotovD. A.ФедотовД. А.
Russian Federation
dmitry.fedotov@medgenetics.ruKashevarovaA. A.КашевароваА. А.
Russian Federation
dmitry.fedotov@medgenetics.ruLebedevI. N.ЛебедевИ. Н.
Russian Federation
dmitry.fedotov@medgenetics.ruTomsk National Research Medical Center of the Russian Academy of SciencesТомский национальный исследовательский медицинский центр Российской академии наук15052024605264126022025Copyright ©; 2024, Russian Academy of SciencesCopyright ©; 2024, Российская академия наук2024Russian Academy of SciencesРоссийская академия наукhttps://transsyst.ru/0016-6758/article/view/667259

This review is devoted to a comprehensive analysis of DNA copy number variations (CNVs) identified in patients with neurodevelopmental disorders (NDDs) from the literature. The selection of publications was conducted using specifically developed criteria. CNVs were characterized based on their clinical significance, type of copy number alteration (microdeletion/microduplication), size, origin, and gene content. The study sample comprised 3,375 patients with NDDs, among whom pathogenic and likely pathogenic CNVs, as well as variants of uncertain clinical significance, were identified in 395 individuals (12%). Chromosomal variations from each category were identified in 89 (3%), 56 (2%), and 241 (7%) patients, respectively. Nine individuals exhibited combinations of CNVs with varying clinical significance. The number of microduplications slightly exceeded the number of deletions (250 and 204, respectively). The size of most CNVs ranged from 193 bp to 400 kb and from 1 to 3 Mb (237 and 96, respectively). Seventy-two variants originated de novo, while 165 were inherited. Eighty-six CNVs were associated with 33 known microdeletion/microduplication syndromes. The most prevalent syndromes included 1q21.1 microduplication (7/395, 1.8%) (OMIM: 612475), 2p16.3 microdeletion (9/395, 2.3%) (OMIM: 614332), 15q13.3 microdeletion (7/395, 1.8%) (OMIM: 612001), 16p11.2 microdeletion (9/395, 2.3%) (OMIM: 611913), and 22q11.2 microduplications (7/395, 1.8%) (OMIM: 608363). Enrichment analysis revealed that pathogenic CNVs, as well as variants of uncertain clinical significance, are enriched in genes associated with abnormal behavioral/neurological phenotypes. Likely pathogenic CNVs included genes linked to disorders of the nervous system and homeostasis/metabolism.

Обзор представляет собой комплексный анализ вариаций числа копий участков ДНК (CNV), обнаруженных у пациентов с нарушениями психомоторного развития (НПР) и опубликованных в мировой литературе, с применением специально разработанных критериев отбора. CNV охарактеризованы в отношении клинической значимости, типа изменения копийности (микроделеции/микродупликации), размера, происхождения и вовлеченных генов. Исследуемая выборка включала 3375 пациентов с НПР, среди которых патогенные и вероятно патогенные CNV, а также варианты с неопределенной клинической значимостью были обнаружены у 395 индивидов (12%). Хромосомные варианты из каждой категории выявлены у 89 (3%), 56 (2%) и 241 (7%) пациентов соответственно. Девять индивидов имели комбинации CNV разной клинической значимости. Количество микродупликаций незначительно преобладает над числом микроделеций (250 и 204 соответственно). Размер большей части CNV варьировал в диапазоне от 193 пар нуклеотидов до 400 кб и от 1 до 3 Мб (237 и 96 соответственно). 72 варианта возникли de novo, 165 были унаследованы. 87 CNV ассоциированы с 33 известными микроделеционными/микродупликационными синдромами. Наиболее часто встречались синдромы микродупликации 1q21.1 (7/395, 1.8%) (OMIM:612475), микроделеции 2p16.3 (9/395, 2.3%) (OMIM:614332), микроделеции 15q13.3 (7/395, 1.8%) (OMIM:612001), микроделеции 16p11.2 (9/395, 2.3%) (OMIM:611913) и микродупликации 22q11.2 (7/395, 1.8%) (OMIM:608363). В результате анализа обогащения было установлено, что патогенные CNV, как и варианты с неопределенной клинической значимостью, обогащены генами, ассоциированными с аномальным поведенческим/неврологическим фенотипом. Вероятно патогенные CNV включали гены, связанные с нарушениями нервной системы, а также гомеостаза/метаболизма.

DNA copy number variation (CNV)neurodevelopment disorder (NDD)intellectual disability (ID)autism spectrum disorder (ASD)attention deficit hyperactivity disorder (ADHD)вариации числа копий участков ДНК (copy number variation, CNV)нарушения психомоторного развития (НПР)интеллектуальные нарушениярасстройства аутистического спектра (РАС)синдром дефицита внимания и гиперактивности (СДВГ)Российский научный фондRussian Science Foundation21-65-00017International Classification of Diseases 11th Revision.The global standard for diagnostic health information. https://icd.who.int/. (Accessed 8 Sep 2023).Ilyas M., Mir A., Efthymiou S., Houlden H. The genetics of intellectual disability: Advancing technology and gene editing // F1000Res. 2020. V. 9. № 22. https://doi.org/10.12688/f1000research.16315.1Kearney H. M., Thorland E. C., Brown K. K. et al. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants // Genet. Med. 2011. V. 13. № 7. P. 680–685. https://doi.org/10.1097/GIM.0b013e3182217a3aAlkan C., Coe B.P., Eichler E.E. Genome structural variation discovery and genotyping // Nat. Rev. Genet. 2011. V. 12. № 5. P. 363–376. https://doi.org/10.1038/nrg2958Lupiáñez D.G., Kraft K., Heinrich V. et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions // Cell. 2015. V. 161. № 5. P. 1012–1025. https://doi.org/10.1016/j.cell.2015.04.004Girirajan S., Rosenfeld J.A., Cooper G.M. et al. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay // Nat. Genet. 2010. V. 42. № 3. P. 203–209. https://doi.org/10.1038/ng.534Cooper D.N., Krawczak M., Polychronakos C. et al. Where genotype is not predictive of phenotype: Towards an understanding of the molecular basis of reduced penetrance in human inherited disease // Hum. Genet. 2013. V. 132. №10. P.1077–1130. https://doi.org/10.1007/s00439-013-1331-2Database of Genomic Variants (DGV). URL: https://dgv.tcag.ca/ (Accessed 8 Sep 2023).Mapping the clinical genome (DECIPHER). https://www.deciphergenomics.org/. (Accessed 8 Sep 2023.Online Mendelian Inheritance in Man (OMIM). https://omim.org/.Page M.J., McKenzie J.E., Bossuyt P.M. et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews // BMJ. 2021. V. 372. № n71. https://doi.org/10.1136/bmj.n71National Library of Medicine, National Center for Bio-technology Information. https://pubmed.nc-bi.nlm.nih.gov/ (Accessed 8 Sep 2023).NCBI Genome Remapping Service (NCBI Remap). URL: https://www.ncbi.nlm.nih.gov/genome/tools/remap (Accessed 8 Sep 2023).Chehbani F., Tomaiuolo P., Picinelli C. et al. Yield of array-CGH analysis in Tunisian children with autism spectrum disorder // Mol. Genet. Genomic Med. 2022. V. 10. №. 8. https://doi.org/10.1002/mgg3.1939Baccarin M., Picinelli C., Tomaiuolo P. et al. Appropriateness of array-CGH in the ADHD clinics: A comparative study // Genes Brain Behav. 2020. V. 19. № 6. https://doi.org/10.1111/gbb.12651Zarrei M., Burton C.L., Engchuan W. et al. A large data resource of genomic copy number variation across neurodevelopmental disorders // NPJ Genom. Med. 2019. V. 4. № 26. https://doi.org/10.1038/s41525-019-0098-3Lindstrand A., Eisfeldt J., Pettersson M. et al. From cytogenetics to cytogenomics: Whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability // Genome Med. 2019. V. 11. №. 68. https://doi.org/10.1186/s13073-019-0675-1Lopes F., Torres F., Soares G. et al. Genomic imbalances defining novel intellectual disability associated loci // Orphanet J. Rare Dis. 2019. V. 14. № 164. https://doi.org/10.1186/s13023-019-1135-0Firouzabadi S.G., Kariminejad R., Vameghi R. et al. Copy number variants in patients with autism and additional clinical features: Report of VIPR2 duplication and a novel microduplication syndrome // Mol. Neurobiol. 2017. V. 54. № 9. P. 7019–7027. https://doi.org/10.1007/s12035-016-0202-yFry A.E., Rees E., Thompson R. et al. Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy // BMC Med. Genet. 2016. V. 17. № 34. https://doi.org/10.1186/s12881-016-0294-2Wilfert A.B., Sulovari A., Turner T.N. et al. Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications // Genome Med. 2017. V. 9. № 101. https://doi.org/10.1186/s13073-017-0498-xMunnich A., Demily C., Frugère L. et al. Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder // Mol. Autism. 2019. V. 10. № 33. https://doi.org/10.1186/s13229-019-0284-2McGowan-Jordan J., Hastings R.J., Moore S. ISCN 2020: An International System for Human Cytogenomic Nomenclature (2020). Basel: Karger, 2020. https://doi.org/10.1159/isbn.978-3-318-06867-2Bonati M.T., Castronovo C., Sironi A. et al. 9q34.3 microduplications lead to neurodevelopmental disorders through EHMT1 overexpression // Neurogenetics. 2019. V. 20. № 3. P. 145–154. https://doi.org/10.1007/s10048-019-00581-6Bailey J.A., Yavor A.M., Massa H.F. et al. Segmental duplications: Organization and impact within the current human genome project assembly // Genome Res. 2001. V. 11. № 6. P. 1005–1017. https://doi.org/10.1101/gr.gr-1871rRedaelli S., Maitz S., Crosti F. et al. Refining the phenotype of recurrent rearrangements of chromosome 16 // Int. J. Mol. Sci. 2019. V. 20. № 5. https://doi.org/10.3390/ijms20051095Delbridge M.L., McMillan D.A., Doherty R.J. et al. Origin and evolution of candidate mental retardation genes on the human X chromosome (MRX) // BMC Genomics. 2008. V. 5. № 9. https://doi.org/10.1186/1471-2164-9-65Беляева Е.О. Клинико-генетическая характеристика пациентов с недифференцированными формами интеллектуальных расстройств и хромосомными микродупликациями: Дис… канд. мед. наук. М.: НИИ мед. генетики ТНИМЦ, 2019. 231 с.Girirajan S., Eichler E.E. Phenotypic variability and genetic susceptibility to genomic disorders // Hum. Mol. Genet. 2010. V. 19. № R2. P. R176–R187. https://doi.org/10.1093/hmg/ddq366Girirajan S., Rosenfeld J.A., Coe B.P. et al. Phenotypic heterogeneity of genomic disorders and rare copy-number variants // N. Engl. J. Med. 2012. V. 367. № 14. P. 1321–1331. https://doi.org/10.1056/NEJMoa1200395Kikas T., Punab A.M., Kasak L. et al. Microdeletions and microduplications linked to severe congenital disorders in infertile men // Sci. Rep. 2023. V. 13. № 574. P. 1–11. https://doi.org/10.1038/s41598-023-27750-wMosley T.J., Johnston H.R., Cutler D.J. et al. Sex-specific recombination patterns predict parent of origin for recurrent genomic disorders // BMC Med. Genomics. 2021. V. 14. № 154. P. 1–12. https://doi.org/10.1186/s12920-021-00999-8Chowdhury R., Bois P.R., Feingold E. et al. Genetic analysis of variation in human meiotic recombination // PLoS Genet. 2009. V. 5. № 9. https://doi.org/10.1371/journal.pgen.1000648Potocki L., Chen K.S., Park S.S. et al. Molecular mechanism for duplication 17p11.2 – the homologous recombination reciprocal of the Smith-Magenis microdeletion // Nat. Genetics. 2000. V. 24. № 1. P. 84–87. https://doi.org/10.1038/71743Gajecka M., Mackay K.L., Shaffer L.G. Monosomy 1p36 deletion syndrome // Am. J. Med. Genet. Part C. Semin. Med. Genet. 2007. V. 145. №. 4. P. 346–356. https://doi.org/10.1002/ajmg.c.30154Delio M., Guo T., McDonald-McGinn D.M. et al. Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes // Am. J. Hum. Genet. 2013. V. 92 № 3. P. 439–447. https://doi.org/10.1016/j.ajhg.2013.01.018Duyzend M.H., Nuttle X., Coe B.P. et al. Maternal modifers and parent-of-origin bias of the autism-associated 16p11.2 CNV // Am. J. Hum. Genet. 2016. V. 98. № 1. P. 45–57. https://doi.org/10.1016/j.ajhg.2015.11.017Neuhausler L., Summerer A., Cooper D.N. et al. Pronounced maternal parent-of-origin bias for type-1 NF1 microdeletions // Hum. Genet. 2018. V. 137. № 5. P. 365–373. https://doi.org/10.1007/s00439-018-1888-xWang B., Ji T., Zhou X. et al. CNV analysis in Chinese children of mental retardation highlights a sex differentiation in parental contribution to de novo and inherited mutational burdens // Sci. Rep. 2016. V. 6. № 25954. https://doi.org/10.1038/srep25954Redon R., Ishikawa S., Fitch K.R. et al. Global variation in copy number in the human genome // Nature. 2006. V. 444. № 7118. P. 444–454. https://doi.org/10.1038/nature05329Itsara A., Cooper G.M., Baker C. et al. Population analysis of large copy number variants and hotspots of human genetic disease // Am. J. Hum. Genet. 2009. V. 84. № 2. P. 148–161. https://doi.org/10.1016/j.ajhg.2008.12.014Cooper G.M., Coe B.P., Girirajan S. et al. A copy number variation morbidity map of developmental delay // Nat. Genetics. 2011. V. 43. № 9. P. 838–846. https://doi.org/10.1038/ng.909Xie Z., Bailey A., Kuleshov M. V. et al. Gene SetKnowledge Discovery with Enrichr // Curr. Protoc. 2021. V. 1. № 3. P. e90. https://doi.org/10.1002/cpz1.90Paz Levy D., Wainstock T., Sheiner E. et al. Maternal recurrent pregnancy loss is associated with an increased risk for long-term neurological morbidity in offspring // Dev. Med. Child Neurol. 2019. V. 61. № 1. P. 91–97. https://doi.org/10.1111/dmcn.13976Wang H., Li F., Miao M. et al. Maternal spontaneous abortion and the risk of attention-deficit/hyperactivity disorder in offspring: A population-based cohort study // Hum. Reprod. 2020. V. 35. № 5. P. 1211–1221. https://doi.org/10.1093/humrep/deaa035Ji H., Yu Y., Miao M. et al. Risk of intellectual disability and maternal history of spontaneous abortion: A nationwide cohort study // Dev. Med. Child Neurol. 2021. V. 63. № 7. P. 831–838. https://doi.org/10.1111/dmcn.14839Levy B., Wapner R. Prenatal diagnosis by chromosomal microarray analysis // Fertil. Steril. 2018. V. 109. № 2. P. 201–212. https://doi.org/10.1016/j.fertnstert.2018.01.005Finley J., Hay S., Oldzej J. et al. The genomic basis of sporadic and recurrent pregnancy loss: a comprehensive in-depth analysis of 24,900 miscarriages // Reprod. Biomed. Online. 2022. V. 45. № 1. P. 125–134. https://doi.org/10.1016/j.rbmo.2022.03.014