CNVs in Patients with Neurodevelopmental Disorders: Meta-Analysis

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Abstract

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.

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About the authors

D. A. Fedotov

Tomsk National Research Medical Center of the Russian Academy of Sciences

Author for correspondence.
Email: dmitry.fedotov@medgenetics.ru
Russian Federation, Tomsk

A. A. Kashevarova

Tomsk National Research Medical Center of the Russian Academy of Sciences

Email: dmitry.fedotov@medgenetics.ru
Russian Federation, Tomsk

I. N. Lebedev

Tomsk National Research Medical Center of the Russian Academy of Sciences

Email: dmitry.fedotov@medgenetics.ru
Russian Federation, Tomsk

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2. Fig. 1. Publication search algorithm (NCBI PubMed) [12]. Last date of circulation - 01.05.2023

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3. Fig. 2. Graph of results of scientific studies included in the meta-analysis and summary data. Study - references to the papers included in the analysis. Events - number of patients with pathogenic CNVs. Total - total number of patients analysed. Graph - effect measures for each of the studies, including confidence intervals, represented by horizontal lines. Rhombus - total effect. Proportion - proportion of patients with pathogenic CNVs in the total sample. Weight - contribution of each study to the meta-analysis [11]

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4. Fig. 3. Distribution of CNVs on chromosomes. On the abscissa axis - chromosome, on the ordinate axis - number of CNVs

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5. Fig. 4. Characterisation of the total spectrum of CNVs in relation to the direction of change in copy number and clinical significance. a - total spectrum; b - pathogenic, probably pathogenic CNVs, variants with uncertain clinical significance

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6. Fig. 5. Origin of CNV. a - pathogenic variants; b - probably pathogenic variants, c - variants with uncertain clinical significance

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7. Fig. 6. CNV size. On the abscissa axis - number of CNVs; on the ordinate axis - CNV size ranges

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