Construction of copy number variation landscape and characterization of associated genes in a Bangladeshi cohort of neurodevelopmental disorders

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Abstract

Introduction: Copy number variations (CNVs) play a critical role in the pathogenesis of neurodevelopmental disorders (NDD) among children. In this study, we aim to identify clinically relevant CNVs, genes and their phenotypic characteristics in an ethnically underrepresented homogenous population of Bangladesh.

Methods: We have conducted chromosomal microarray analysis (CMA) for 212 NDD patients with male to female ratio of 2.2:1.0 to identify rare CNVs. To identify candidate genes within the rare CNVs, gene constraint metrics [i.e., “Critical-Exon Genes (CEGs)”] were applied to the population data. Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) was followed in a subset of 95 NDD patients to assess the severity of autism and all statistical tests were performed using the R package.

Results: Of all the samples assayed, 12.26% (26/212) and 57.08% (121/212) patients carried pathogenic and variant of uncertain significance (VOUS) CNVs, respectively. While 2.83% (6/212) patients’ pathogenic CNVs were found to be located in the subtelomeric regions. Further burden test identified females are significant carriers of pathogenic CNVs compared to males (OR = 4.2; p = 0.0007). We have observed an increased number of Loss of heterozygosity (LOH) within cases with 23.85% (26/109) consanguineous parents. Our analyses on imprinting genes show, 36 LOH variants disrupting 69 unique imprinted genes and classified these variants as VOUS. ADOS-2 subset shows severe social communication deficit ( p = 0.014) and overall ASD symptoms severity ( p = 0.026) among the patients carrying duplication CNV compared to the CNV negative group. Candidate gene analysis identified 153 unique CEGs in pathogenic CNVs and 31 in VOUS. Of the unique genes, 18 genes were found to be in smaller (<1 MB) focal CNVs in our NDD cohort and we identified PSMC3 gene as a strong candidate gene for Autism Spectrum Disorder (ASD). Moreover, we hypothesized that KMT2B gene duplication might be associated with intellectual disability.

Conclusion: Our results show the utility of CMA for precise genetic diagnosis and its integration into the diagnosis, therapy and management of NDD patients.

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Martin Krzywinski, Jacqueline Schein, Inanç Birol … (2009)

We created a visualization tool called Circos to facilitate the identification and analysis of similarities and differences arising from comparisons of genomes. Our tool is effective in displaying variation in genome structure and, generally, any other kind of positional relationships between genomic intervals. Such data are routinely produced by sequence alignments, hybridization arrays, genome mapping, and genotyping studies. Circos uses a circular ideogram layout to facilitate the display of relationships between pairs of positions by the use of ribbons, which encode the position, size, and orientation of related genomic elements. Circos is capable of displaying data as scatter, line, and histogram plots, heat maps, tiles, connectors, and text. Bitmap or vector images can be created from GFF-style data inputs and hierarchical configuration files, which can be easily generated by automated tools, making Circos suitable for rapid deployment in data analysis and reporting pipelines.

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Integration of biological networks and gene expression data using Cytoscape.

Melissa Cline, Michael Smoot, Ethan Cerami … (2007)

Cytoscape is a free software package for visualizing, modeling and analyzing molecular and genetic interaction networks. This protocol explains how to use Cytoscape to analyze the results of mRNA expression profiling, and other functional genomics and proteomics experiments, in the context of an interaction network obtained for genes of interest. Five major steps are described: (i) obtaining a gene or protein network, (ii) displaying the network using layout algorithms, (iii) integrating with gene expression and other functional attributes, (iv) identifying putative complexes and functional modules and (v) identifying enriched Gene Ontology annotations in the network. These steps provide a broad sample of the types of analyses performed by Cytoscape.

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ClinVar: public archive of interpretations of clinically relevant variants

Melissa J. Landrum, Jennifer Lee, Mark Benson … (2015)

ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) at the National Center for Biotechnology Information (NCBI) is a freely available archive for interpretations of clinical significance of variants for reported conditions. The database includes germline and somatic variants of any size, type or genomic location. Interpretations are submitted by clinical testing laboratories, research laboratories, locus-specific databases, OMIM®, GeneReviews™, UniProt, expert panels and practice guidelines. In NCBI's Variation submission portal, submitters upload batch submissions or use the Submission Wizard for single submissions. Each submitted interpretation is assigned an accession number prefixed with SCV. ClinVar staff review validation reports with data types such as HGVS (Human Genome Variation Society) expressions; however, clinical significance is reported directly from submitters. Interpretations are aggregated by variant-condition combination and assigned an accession number prefixed with RCV. Clinical significance is calculated for the aggregate record, indicating consensus or conflict in the submitted interpretations. ClinVar uses data standards, such as HGVS nomenclature for variants and MedGen identifiers for conditions. The data are available on the web as variant-specific views; the entire data set can be downloaded via ftp. Programmatic access for ClinVar records is available through NCBI's E-utilities. Future development includes providing a variant-centric XML archive and a web page for details of SCV submissions.

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Author and article information

Contributors

Md. Robed Amin: URI : https://loop.frontiersin.org/people/1842134/overview

Md. Ashrafur Rahman: URI : https://loop.frontiersin.org/people/2033263/overview

Md. Ismail Hosen: URI : https://loop.frontiersin.org/people/407102/overview

Noushad Karuvantevida: URI : https://loop.frontiersin.org/people/494112/overview

A. H. M. Nurun Nabi: URI : https://loop.frontiersin.org/people/391240/overview

Mohammed Uddin: URI : https://loop.frontiersin.org/people/1066022/overview

Journal

Journal ID (nlm-ta): Front Genet

Journal ID (iso-abbrev): Front Genet

Journal ID (publisher-id): Front. Genet.

Title: Frontiers in Genetics

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-8021

Publication date (Electronic): 07 March 2023

Publication date Collection: 2023

Volume: 14

Electronic Location Identifier: 955631

Affiliations

[1] ¹ Genetics and Genomic Medicine Centre , NeuroGen Healthcare , Dhaka, Bangladesh

[2] ² Department of Biochemistry and Molecular Biology , University of Dhaka , Dhaka, Bangladesh

[3] ³ Department of Paediatric Neurology , Bangabandhu Sheikh Mujib Medical University , Dhaka, Bangladesh

[4] ⁴ Department of Child Neurology , NeuroGen Healthcare , Dhaka, Bangladesh

[5] ⁵ Department of Paediatric Neuroscience , Dhaka Shishu Hospital , Dhaka, Bangladesh

[6] ⁶ Department of Neurology , National Institute of Neurosciences and Hospital , Dhaka, Bangladesh

[7] ⁷ Centre for Precision Therapeutics , NeuroGen Healthcare , Dhaka, Bangladesh

[8] ⁸ Institute of Plant Genetics , Department of Plant Biotechnology , Leibniz University Hannover , Hanover, Germany

[9] ⁹ Department of Medicine , Dhaka Medical College , Dhaka, Bangladesh

[10] ¹⁰ Department of Paediatric Neurology , National Institute of Neuroscience and Hospital , Dhaka, Bangladesh

[11] ¹¹ Department of Biology and Biochemistry , University of Houston , Houston, TX, United States

[12] ¹² Cellular Intelligence Lab , GenomeArc Inc , Toronto, ON, Canada

[13] ¹³ Department of Child Neurology , Bangabandhu Sheikh Mujib Medical University , Dhaka, Bangladesh

[14] ¹⁴ Department of Obstetrics and Gynaecology , Bangabandhu Sheikh Mujib Medical University , Dhaka, Bangladesh

[15] ¹⁵ Department of Pharmaceutical Sciences , Wilkes University , Pennsylvania, PA, United States

[16] ¹⁶ Department of Biomedical Engineering , Military Institute of Science and Technology , Dhaka, Bangladesh

[17] ¹⁷ Department of Paediatrics , BIRDEM General Hospital , Dhaka, Bangladesh

[18] ¹⁸ College of Medicine , Mohammed Bin Rashid University of Medicine and Health Sciences , Dubai, United Arab Emirates

[19] ¹⁹ Department of Biochemistry , Holy Family Red Crescent Medical College , Dhaka, Bangladesh

[20] ²⁰ Cellular Intelligence (Ci) Lab , GenomeArc Inc , Toronto, ON, Canada

Author notes

Edited by: Sarah H. Elsea, Baylor College of Medicine, United States

Reviewed by: Gyorgy Fekete, Semmelweis University, Hungary

Ankita Patel, Fulgent Genetics, United States

*Correspondence: Mohammed Uddin, mohammed.uddin@ 123456mbru.ac.ae

[ † ]

These authors share first authorship

This article was submitted to Neurogenomics, a section of the journal Frontiers in Genetics

Article

Publisher ID: 955631

DOI: 10.3389/fgene.2023.955631

PMC ID: 10028086

PubMed ID: 36959829

SO-VID: 1a59899f-255e-4b91-a532-9cb3c6a4055e

Copyright © Copyright © 2023 Akter, Rahman, Sarker, Basiruzzaman, Islam, Rahaman, Rahaman, Eshaque, Dity, Sarker, Amin, Hossain, Lopa, Jahan, Hossain, Islam, Mondol, Faruk, Saha, Kundu, Kanta, Kazal, Fatema, Rahman, Hasan, Hossain Mollah, Hosen, Karuvantevida, Begum, Zehra, Nassir, Nabi, Uddin and Uddin.

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 29 May 2022

Date accepted : 14 February 2023

Funding

Funded by: Mohammed Bin Rashid University of Medicine and Health Sciences , doi 10.13039/501100020917;

This work was supported, in whole or in part, by internal grant awards from Startup Bangladesh—iDEA project; Genetics and Genomic Medicine Centre, NeuroGen Healthcare; Bangabandhu Science and Technology Fellowship Trust (BSTFT); Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU)—College of Medicine; Sandooq Al Watan Research and Development Grant (SWARD-F2018-002); and AlMahmeed Collaborative Research Awards (ALM 1801 and ALM 20-0074). NN was supported by MBRU Post-Doctoral Fellow Award (MBRU-PD-2020-02).

Construction of copy number variation landscape and characterization of associated genes in a Bangladeshi cohort of neurodevelopmental disorders

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G3: Genes|Genomes|Genetics

Most cited references 95

Circos: an information aesthetic for comparative genomics.

Integration of biological networks and gene expression data using Cytoscape.

ClinVar: public archive of interpretations of clinically relevant variants

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