RESUMO
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.
RESUMO
LAY ABSTRACT: A nationwide survey was done in Bangladesh to assess autism spectrum disorder prevalence in 16- to 30-month-old children at urban-rural distribution and to determine the association with socioeconomic and demographic conditions. A three-stage cluster sampling method was used where districts from all divisions were selected in the first stage, census enumeration areas as blocks of households were selected in the second stage and households (within the blocks) were selected in the third stage. Thereby, it included 38,440 children from 37,982 households (71% rural, 29% urban) aged 16-30 months from 30 districts of eight divisions of Bangladesh. Screening was done with a 'Red Flag' tool and Modified Checklist for Toddlers and a final diagnosis using Diagnostic and Statistical Manual of Mental Disorders, 5th Edition for autism spectrum disorder. Autism spectrum disorder prevalence was 17 per 10,000 young children - in other words, one in 589 young children. Boys were found at higher risk of autism (one in 423 boys; one in 1026 girls). Prevalence of autism spectrum disorder was higher in urban environments than in rural ones - 25/10,000 and 14/10,000, respectively. More autism spectrum disorder children were found in advanced age groups of parents, especially mothers, and in households with a higher wealth quintile. This survey is significant as it covers both urban and rural areas and specifically targets very young children. The involvement of the Bangladesh Bureau of Statistics, as well as support from the entire healthcare system infrastructure, makes this survey more representative on a national level. Its results will form a database to support the development of an effective early intervention programme in Bangladesh. We hope it will prove useful for researchers, clinicians and frontline healthcare workers, and inform the decisions of policymakers and funders in Bangladesh.
RESUMO
Background: Autism spectrum disorder (ASD) refers to a group of complex neurodevelopment disorders characterized by repetitive and characteristic patterns of behavior and difficulties with social communication and interaction. In Bangladesh, autism in children is a significant burden of disease. Early identification of ASD could improve quality of life. The study has explored at the prevalence of ASD among rural community children aged between 18-36 months. Methods: A cross sectional study was conducted among the 5286 children aged between 18-36 months in a rural community. Household level data was collected using screening tool MCHAT. Primarily screening positive 66 children were invited for final diagnosis in a health camp. Diagnosis was made by different staging started from primary screening, followed by validation using MCHAT and flash card. Final diagnosis was made by the paediatric neurologists, child clinical psychologists and development therapist using diagnostic tools (DSM-IV & ADOS). Results: 04 children were diagnosed with autism spectrum disorder (ASD). Prevalence of the ASD in rural community was found 0.75/1000 children. Among the four ASD cases three were boys and one was girl and age range was between 20- 30 months. Whereas, the highest prevalence rate found was for the cerebral palsy which was 5.6/1000 children and Developmental delay (2.6/1000) was the next to that. Conclusions: Age specific autism (18-36 months) in children is found higher in rural community of Bangladesh. In order to get more comprehensive information on autism in other age groups of children in rural community, further study is required. Early detection in rural community could help the policy makers to decentralization of health services among the ASD children in rural community.