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

被引：8

作者：

Akter, Hosneara ^{[1
,2
]}

Rahman, Muhammad Mizanur ^{[3
]}

Sarker, Shaoli ^{[4
,5
]}

Basiruzzaman, Mohammed ^{[4
,6
]}

Islam, Md. Mazharul ^{[4
,6
]}

Rahaman, Md. Atikur ^{[1
]}

Rahaman, Md. Ashiquir ^{[7
]}

Eshaque, Tamannyat Binte ^{[1
]}

Dity, Nushrat Jahan ^{[1
]}

Sarker, Shouvik ^{[8
]}

Amin, Md. Robed ^{[9
]}

Hossain, Mohammad Monir ^{[10
]}

Lopa, Maksuda ^{[7
]}

Jahan, Nargis ^{[7
]}

Hossain, Shafaat ^{[11
]}

Islam, Amirul ^{[1
,12
]}

Mondol, Ashaduzzaman ^{[7
]}

Faruk, Md Omar ^{[7
]}

Saha, Narayan ^{[10
]}

Kundu, Gopen Kumar ^{[13
]}

Kanta, Shayla Imam ^{[5
]}

Kazal, Rezaul Karim ^{[14
]}

Fatema, Kanij ^{[3
]}

Rahman, Md. Ashrafur ^{[15
]}

Hasan, Maruf ^{[16
]}

Mollah, Md. Abid Hossain ^{[17
]}

Hosen, Md. Ismail ^{[2
]}

Karuvantevida, Noushad ^{[18
]}

Begum, Ghausia ^{[18
]}

Zehra, Binte ^{[18
]}

Nassir, Nasna ^{[18
]}

Nabi, A. H. M. Nurun ^{[2
]}

Uddin, K. M. Furkan ^{[1
,19
]}

Uddin, Mohammed ^{[18
,20
]}

机构：

[1] NeuroGen Healthcare, Genet & Genom Med Ctr, Dhaka, Bangladesh

[2] Univ Dhaka, Dept Biochem & Mol Biol, Dhaka, Bangladesh

[3] Bangabandhu Sheikh Mujib Med Univ, Dept Paediat Neurol, Dhaka, Bangladesh

[4] NeuroGen Healthcare, Dept Child Neurol, Dhaka, Bangladesh

[5] Dhaka Shishu Hosp, Dept Paediat Neurosci, Dhaka, Bangladesh

[6] Natl Inst Neurosci & Hosp, Dept Neurol, Dhaka, Bangladesh

[7] NeuroGen Healthcare, Ctr Precis Therapeut, Dhaka, Bangladesh

[8] Leibniz Univ Hannover, Inst Plant Genet, Dept Plant Biotechnol, Hannover, Germany

[9] Dhaka Med Coll, Dept Med, Dhaka, Bangladesh

[10] Natl Inst Neurosci & Hosp, Dept Paediat Neurol, Dhaka, Bangladesh

[11] Univ Houston, Dept Biol & Biochem, Houston, TX USA

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

[13] Bangabandhu Sheikh Mujib Med Univ, Dept Child Neurol, Dhaka, Bangladesh

[14] Bangabandhu Sheikh Mujib Med Univ, Dept Obstet & Gynaecol, Dhaka, Bangladesh

[15] Wilkes Univ, Dept Pharmaceut Sci, Wilkes Barre, PA USA

[16] Mil Inst Sci & Technol, Dept Biomed Engn, Dhaka, Bangladesh

[17] BIRDEM Gen Hosp, Dept Paediat, Dhaka, Bangladesh

[18] Mohammed Bin Rashid Univ Med & Hlth Sci, Coll Med, Dubai, U Arab Emirates

[19] Holy Family Red Crescent Med Coll, Dept Biochem, Dhaka, Bangladesh

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

来源：

FRONTIERS IN GENETICS | 2023年 / 14卷

关键词：

neurodevelopmental disorders (NDDs); chromosomal microarray analysis (CMA); copy number variation (CNV); Autism Diagnostic Observation Schedule-Second Edition (ADOS-2); variant of uncertain significance (VOUS); critical exon gene (CEG); autism spectrum disorder (ASD); GENOME-WIDE ASSOCIATION; DEVELOPMENTAL DELAY; PRADER-WILLI; AUTISM; MICROARRAY; MUTATIONS; DELETION; DISEASE; KMT2B; HAPLOINSUFFICIENCY;

D O I：

10.3389/fgene.2023.955631

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页数：18

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