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

Autor:	Akter H; Genetics and Genomic Medicine Centre, NeuroGen Healthcare, Dhaka, Bangladesh.; Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh., Rahman MM; Department of Paediatric Neurology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh., Sarker S; Department of Child Neurology, NeuroGen Healthcare, Dhaka, Bangladesh.; Department of Paediatric Neuroscience, Dhaka Shishu Hospital, Dhaka, Bangladesh., Basiruzzaman M; Department of Child Neurology, NeuroGen Healthcare, Dhaka, Bangladesh.; Department of Neurology, National Institute of Neurosciences and Hospital, Dhaka, Bangladesh., Islam MM; Department of Child Neurology, NeuroGen Healthcare, Dhaka, Bangladesh.; Department of Neurology, National Institute of Neurosciences and Hospital, Dhaka, Bangladesh., Rahaman MA; Genetics and Genomic Medicine Centre, NeuroGen Healthcare, Dhaka, Bangladesh., Rahaman MA; Centre for Precision Therapeutics, NeuroGen Healthcare, Dhaka, Bangladesh., Eshaque TB; Genetics and Genomic Medicine Centre, NeuroGen Healthcare, Dhaka, Bangladesh., Dity NJ; Genetics and Genomic Medicine Centre, NeuroGen Healthcare, Dhaka, Bangladesh., Sarker S; Institute of Plant Genetics, Department of Plant Biotechnology, Leibniz University Hannover, Hanover, Germany., Amin MR; Department of Medicine, Dhaka Medical College, Dhaka, Bangladesh., Hossain MM; Department of Paediatric Neurology, National Institute of Neuroscience and Hospital, Dhaka, Bangladesh., Lopa M; Centre for Precision Therapeutics, NeuroGen Healthcare, Dhaka, Bangladesh., Jahan N; Centre for Precision Therapeutics, NeuroGen Healthcare, Dhaka, Bangladesh., Hossain S; Department of Biology and Biochemistry, University of Houston, Houston, TX, United States., Islam A; Genetics and Genomic Medicine Centre, NeuroGen Healthcare, Dhaka, Bangladesh.; Cellular Intelligence Lab, GenomeArc Inc, Toronto, ON, Canada., Mondol A; Centre for Precision Therapeutics, NeuroGen Healthcare, Dhaka, Bangladesh., Faruk MO; Centre for Precision Therapeutics, NeuroGen Healthcare, Dhaka, Bangladesh., Saha N; Department of Paediatric Neurology, National Institute of Neuroscience and Hospital, Dhaka, Bangladesh., Kundu GK; Department of Child Neurology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh., Kanta SI; Department of Paediatric Neuroscience, Dhaka Shishu Hospital, Dhaka, Bangladesh., Kazal RK; Department of Obstetrics and Gynaecology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh., Fatema K; Department of Paediatric Neurology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh., Rahman MA; Department of Pharmaceutical Sciences, Wilkes University, Pennsylvania, PA, United States., Hasan M; Department of Biomedical Engineering, Military Institute of Science and Technology, Dhaka, Bangladesh., Hossain Mollah MA; Department of Paediatrics, BIRDEM General Hospital, Dhaka, Bangladesh., Hosen MI; Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh., Karuvantevida N; College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates., Begum G; College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates., Zehra B; College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates., Nassir N; College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates., Nabi AHMN; Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh., Uddin KMF; Genetics and Genomic Medicine Centre, NeuroGen Healthcare, Dhaka, Bangladesh.; Department of Biochemistry, Holy Family Red Crescent Medical College, Dhaka, Bangladesh., Uddin M; College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates.; Cellular Intelligence (Ci) Lab, GenomeArc Inc, Toronto, ON, Canada.
Jazyk:	angličtina
Zdroj:	Frontiers in genetics [Front Genet] 2023 Mar 07; Vol. 14, pp. 955631. Date of Electronic Publication: 2023 Mar 07 (Print Publication: 2023).
DOI:	10.3389/fgene.2023.955631
Abstrakt:	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. Competing Interests: Authors AI and MU are employees of GenomeArc Inc. Authors HA, SLS, MB, MMI, MAR(1), MAR(2), TBE, NJD, ML, NJ, AI, AM, MOF, and KMFU are employees of NeuroGen Healthcare. The authors declare that this study received funding from NeuroGen Healthcare. The funder was not involved in the study design, collection, analysis, interpretation of data, and the writing of this article or the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (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.)
Databáze:	MEDLINE
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