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.
This study was aimed at evaluating the association between gestational diabetes mellitus (GDM) and fetal birth weight considering duration of pregnancy, maternal age and body mass index (BMI). This was a retrospective cross-sectional study followed by cohort type of study. Initially, pregnant women in their 24 to 28th week of gestation were selected for determining their fasting blood glucose (FBG) level and blood glucose level 2 hrs after 75 g oral glucose intake. The cut-off value for the diagnosis of GDM was > 5.3 mmol/l for FBG level and > 8.6 mmol/l for taking 75 g oral glucose intake after 2 hrs. Both GDM and control group subjects were followed up to neonatal period to find out neonatal outcomes. Among the total 215 subjects, 84 pregnant women were selected with GDM and rest 131 were control. It is found that GDM alone had a significant (p = 0.05) positive effect on both the duration of pregnancy and fetal birth weight, but not on maternal BMI. Both the effects of duration of pregnancy and GDM are considered together on fetal birth weight, only GDM had significant impact on fetal birth weight compared to the control group. Similarly, when the effect of maternal BMI and GDM is considered together on fetal birth weight, only GDM group was found to have significant effect on fetal birth weight. Parallel results were observed for the effect of both maternal age and GDM on fetal birth weight. In binary logistic regression analysis, when the differences are considered in maternal age, duration of pregnancy and maternal BMI along with GDM, both maternal age ≥ 35 years (OR: 9.43, p = 0.001) and GDM (OR: 10.60, p = 0.003) was found to have significant positive effect on fetal birth weight. It was found that the GDM showed significant influence on fetal birth weight considering the effects of maternal age, duration of pregnancy and maternal BMI. Dhaka Univ. J. Biol. Sci. 29(2): 209-218, 2020 (July)
Background: Copy number variations (CNVs) play a critical role into 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 genome-wide chromosomal microarray analysis (CMA) for 212 NDD patients with male to female ratio of 2.2:1.0 to identify rare chromosomal abnormalities (deletion /duplication/ rearrangements). To identify candidate genes within the rare CNVs, multiple 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 R package. Results: In our cohort, the head circumference of males are significantly greater than females (p=0.0002). Of all samples assayed, 12.26% (26/212) and 47.17% (100/212) patients carried pathogenic and variant of uncertain significance (VOUS) CNVs, respectively. 2.83% (6/212) pathogenic CNVs are located at the subtelomeric regions. Further burden test identified females are significant carriers of pathogenic CNVs in comparison to males (OR=4.2; p=0.0007). ADOS-2 subset show 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 and identified PSMC3 gene as a potential 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 therapeutics and management of NDD patients.
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