Construction of copy number variation landscape and characterization of associated genes in a Bangladeshi cohort of neurodevelopmental disorders
Creators: name: Akter, Hosneara
name: Rahman, Muhammad Mizanur
name: Sarker, Shaoli
name: Basiruzzaman, Mohammed
name: Islam, Md. Mazharul
name: Rahaman, Md. Atikur
name: Rahaman, Md. Ashiquir
name: Eshaque, Tamannyat Binte
name: Dity, Nushrat Jahan
name: Sarker, Shouvik
name: Amin, Md. Robed
name: Hossain, Mohammad Monir
name: Lopa, Maksuda
name: Jahan, Nargis
name: Hossain, Shafaat
name: Islam, Amirul
name: Mondol, Ashaduzzaman
name: Faruk, Md Omar
name: Saha, Narayan
name: Kundu, Gopen Kumar
name: Kanta, Shayla Imam
name: Kazal, Rezaul Karim
name: Fatema, Kanij
name: Rahman, Md. Ashrafur
name: Hasan, Maruf
name: Hossain Mollah, Md. Abid
name: Hosen, Md. Ismail
name: Karuvantevida, Noushad
name: Begum, Ghausia
name: Zehra, Binte
name: Nassir, Nasna
name: Nabi, A. H. M. Nurun
name: Uddin, K. M. Furkan
name: Uddin, Mohammed
Publisher: name: Lausanne : Frontiers Media
Year: 2023
Subjects: subject: Autism Diagnostic Observation Schedule-Second Edition (ADOS-2)
subject: autism spectrum disorder (ASD)
subject: chromosomal microarray analysis (CMA)
subject: copy number variation (CNV)
subject: critical exon gene (CEG)
subject: neurodevelopmental disorders (NDDs)
subject: variant of uncertain significance (VOUS)
subject: Dewey Decimal Classification::500 | Naturwissenschaften::570 | Biowissenschaften, Biologie

description: 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 (&lt;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.