Expanding deep phenotypic spectrum associated with atypical pathogenic structural variations overlapping 15q11-q13 imprinting region.

BACKGROUND: The 15q11-q13 region is a genetic locus with genes subject to genomic imprinting, significantly influencing neurodevelopment. Genomic imprinting is an epigenetic phenomenon that causes differential gene expression based on the parent of origin. In most diploid organisms, gene expression typically involves an equal contribution from both maternal and paternal alleles, shaping the phenotype. Nevertheless, in mammals, including humans, mice, and marsupials, the functional equivalence of parental alleles is not universally maintained. Notably, during male and female gametogenesis, parental alleles may undergo differential marking or imprinting, thereby modifying gene expression without altering the underlying DNA sequence. Neurodevelopmental disorders, such as Prader-Willi syndrome (PWS) (resulting from the absence of paternally expressed genes in this region), Angelman syndrome (AS) (associated with the absence of the maternally expressed UBE3A gene), and 15q11-q13 duplication syndrome (resulting from the two common forms of duplications-either an extra isodicentric 15 chromosome or an interstitial 15 duplication), are the outcomes of genetic variations in this imprinting region. METHODS: Conducted a genomic study to identify the frequency of pathogenic variants impacting the 15q11-q13 region in an ethnically homogenous population from Bangladesh. Screened all known disorders from the DECIPHER database and identified variant enrichment within this cohort. Using the Horizon analysis platform, performed enrichment analysis, requiring at least >60% overlap between a copy number variation and a disorder breakpoint. Deep clinical phenotyping was carried out through multiple examination sessions to evaluate a range of clinical symptoms. RESULTS: This study included eight individuals with clinically suspected PWS/AS, all previously confirmed through chromosomal microarray analysis, which revealed chromosomal breakpoints within the 15q11-q13 region. Among this cohort, six cases (75%) exhibited variable lengths of deletions, whereas two cases (25%) showed duplications. These included one type 2 duplication, one larger atypical duplication, one shorter type 2 deletion, one larger type 1 deletion, and four cases with atypical deletions. Furthermore, thorough clinical assessments led to the diagnosis of four PWS patients, two AS patients, and two individuals with 15q11-q13 duplication syndrome. CONCLUSION: Our deep phenotypic observations identified a spectrum of clinical features that overlap and are unique to PWS, AS, and Dup15q syndromes. Our findings establish genotype-phenotype correlation for patients impacted by variable structural variations within the 15q11-q13 region.

Mutational spectrum and phenotypic variability of Duchenne muscular dystrophy and related disorders in a Bangladeshi population.

Duchenne muscular dystrophy (DMD) is a severe rare neuromuscular disorder caused by mutations in the X-linked dystrophin gene. Several mutations have been identified, yet the full mutational spectrum, and their phenotypic consequences, will require genotyping across different populations. To this end, we undertook the first detailed genotype and phenotype characterization of DMD in the Bangladeshi population. We investigated the rare mutational and phenotypic spectrum of the DMD gene in 36 DMD-suspected Bangladeshi participants using an economically affordable diagnostic strategy involving initial screening for exonic deletions in the DMD gene via multiplex PCR, followed by testing PCR-negative patients for mutations using whole exome sequencing. The deletion mapping identified two critical DMD gene hotspot regions (near proximal and distal ends, spanning exons 8-17 and exons 45-53, respectively) that comprised 95% (21/22) of the deletions for this population cohort. From our exome analysis, we detected two novel pathogenic hemizygous mutations in exons 21 and 42 of the DMD gene, and novel pathogenic recessive and loss of function variants in four additional genes: SGCD, DYSF, COL6A3, and DOK7. Our phenotypic analysis showed that DMD suspected participants presented diverse phenotypes according to the location of the mutation and which gene was impacted. Our study provides ethnicity specific new insights into both clinical and genetic aspects of DMD.

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

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.

Occupational stress and health risk of employees working in the garments sector of Bangladesh: An empirical study.

The present study was conducted with a view to examining the impact of occupational stress on employees' health risk. A total number of 350 garment employees (114 supervisors and 236 workers) were selected from 25 readymade garment factories of Dhaka, Narayanganj, and Gazipur industrial areas of Bangladesh on a random sampling basis. Occupational stress was estimated using an ERIs modified questionnaire; when self-reported health problems, work related information and socio-demographic information were obtained using face-to-face interviews using a pre-formed questionnaire. The survey was conducted for 2 years from January 2020 to December 2021 in Dhaka, Narayanganj and Gazipur districts where most of the garment industries in Bangladesh are located. All data were processed by using Statistical Package for Social Sciences (SPSS) and Decision Analyst Stats, Version 2.0. For analyzing data, suitable statistical tools such as two-way ANOVA, z-test, chi-square test, Pearson's product-moment correlation, stepwise multiple regressions, and descriptive statistics were used. The results of the present study reveal that the occupational stress had a significant positive influence on health risk. The findings also reveal that both the male and female employees perceived garment job highly stressful and risky for their health causes many dies and sickness, but it was higher among the female employees than their counterparts. Study suggests that due to major illness and diseases garments' employees are lacks of sound health that have to consider remedying for reducing occupational stress and health risk.

The interplay between eWOM information and purchase intention on social media: Through the lens of IAM and TAM theory.

The maturity and growth of social media have empowered online customers to generate electronic word of mouth (eWOM), on various online websites and platforms, which may influence an individual's decision-making process. This paper explores eWOM information's impact on social media users' purchase intention by applying the information adoption model (IAM) and the technology acceptance model (TAM). PLS-SEM (SmartPLS V.3.3) has been utilized to test the hypotheses using data of 432 respondents. The research findings evinced that eWOM information quality, credibility, usefulness, and ease of use have been critical in determining online consumers' intention to adopt eWOM and form purchase behavior on social media. The study's outcomes offer the marketing managers a viewpoint to realize the significance of the effect of eWOM information on online purchase intention among social media users. Furthermore, the study findings will also enlighten marketing and business managers to utilize social media websites by gauging consumer behavior and focusing on characteristics of eWOM information on social media for better consumer insights.

Determinants of patients' satisfaction and trust toward healthcare service environment in general practice clinics.

This study aimed to examine the healthcare service environment, patients' experience, and responses toward healthcare services in private general practice (GP) clinics. Self-administered questionnaires were used for collecting data from 367 respondents with prior experience in visiting the general practice clinics in Malaysia. SmartPLS statistical tool was used to test the underlying hypotheses. The results revealed that ambiance, service delivery, interior decor, and cleanliness had a significant influence on patients' trust and satisfaction while the exterior design is neither associated with satisfaction nor trust. Patients' satisfaction and trust had a higher significant effect on their repatronage intention, willingness to pay for a premium healthcare service, and engagement in word-of-mouth for healthcare services. In practice, both the service delivery and ambiance features of the healthcare services environment might be optimized by GP clinics. This research provides significant insights from the patients' perspective toward the GP clinics' healthcare services environment.

Is there a relationship between natural gas consumption and the environmental Kuznets curve? Empirical evidence from Bangladesh.

Bangladesh has significant natural gas reserves, and total demand has climbed substantially in recent years. The study uses the autoregressive distributed lag (ARDL) model for cointegration and the vector autoregressive(VAR) Granger causality model to analyze a long-run link between natural gas (NG) consumption, economic development, urbanization, and CO2 emissions. The objective is to investigate the relationship between the environmental Kuznets curve (EKC) and Bangladesh's NG consumption using data from the years 1990 to 2018. According to the ARDL model, economic growth, urbanization, and NG consumption, all have a positive and significant influence on CO2 emissions. Despite having a negative coefficient, the square of economic development has a significant impact on CO2 emissions. In the long run, it verifies the EKC hypothesis in Bangladesh. Both linear and nonlinear economic development determinants display statistically significant positive and negative signals in the short run. From Bangladesh's perspective, this also demonstrates the presence of an EKC. The impact of NG consumption in the short run is insignificant; nevertheless, urbanization has a significant effect. The VAR Granger causality demonstrates that economic development and urbanization have a bidirectional response; however, NG consumption and CO2 emissions have just one-way causality. The key policy implication of the study is that NG use is expected to raise emissions. Increasing the share of clean energy in the energy utilization system, such as nuclear power and renewable energy, is a plausible policy choice.

The impact of foreign direct investment, tourism, electricity consumption, and economic development on CO2 emissions in Bangladesh.

The study's goal is to investigate the impact of foreign direct investment (FDI), tourism, electricity consumption, and economic development on CO2 emissions in Bangladesh between 1990 and 2019. Empirical results reveal that FDI, electricity consumption, and economic development variables have significant and positive long-term effects on CO2 emissions. Tourism, on the other hand, has a long-term negative effect. The square of the GDP variable has a substantial negative coefficient. This indicates that in Bangladesh, the nexus between CO2 emissions and economic development is U-shaped inverted. As a result, the EKC postulate is proven to be correct. In the short term, electricity consumption, economic development, GDP2, and tourism have no substantial effect on CO2 emissions. Only the coefficients of FDI are negative and significant. The expected ECM coefficients are also negative and statistically significant. According to these data, the system as a whole adjusts at a rate of 60%. The Granger causality study reveals one direction of causation between electricity consumption and CO2 emissions, CO2 emissions and economic development, electricity consumption and economic development, FDI, and CO2 emissions.

Effect of Covid-19 pandemic on tourist travel risk and management perceptions.

This study aims to explore the impact of the Covid-19 pandemic on tourists' travel risk and management perceptions. Driven on the effect of the pandemic, we investigate tourists' travel risk and management perceptions and its effect on society using a sample of 716 respondents. The data was collected through social media platforms using a representative sampling method and analyzed applying the PLS-SEM tool. The findings reveal that Covid-19 pandemic has greatly affected travel risk and management perceptions. Travel risk and management perception had a significant association with risk management, service delivery, transportation patterns, distribution channels, avoidance of overpopulated destinations, and hygiene and safety. The results also identified the mediating effect of travel risk and management perceptions. The finding of this study contributes to tourism crises and provides future research insights in the travel and tourism sector and response to change tourists' travel risk and management perceptions in the post-covid recovery period.

Whole exome sequencing uncovered highly penetrant recessive mutations for a spectrum of rare genetic pediatric diseases in Bangladesh.

Collectively, rare genetic diseases affect a significant number of individuals worldwide. In this study, we have conducted whole-exome sequencing (WES) and identified underlying pathogenic or likely pathogenic variants in five children with rare genetic diseases. We present evidence for disease-causing autosomal recessive variants in a range of disease-associated genes such as DHH-associated 46,XY gonadal dysgenesis (GD) or 46,XY sex reversal 7, GNPTAB-associated mucolipidosis II alpha/beta (ML II), BBS1-associated Bardet-Biedl Syndrome (BBS), SURF1-associated Leigh Syndrome (LS) and AP4B1-associated spastic paraplegia-47 (SPG47) in unrelated affected members from Bangladesh. Our analysis pipeline detected three homozygous mutations, including a novel c. 863 G > C (p.Pro288Arg) variant in DHH, and two compound heterozygous variants, including two novel variants: c.2972dupT (p.Met991Ilefs*) in GNPTAB and c.229 G > C (p.Gly77Arg) in SURF1. All mutations were validated by Sanger sequencing. Collectively, this study adds to the genetic heterogeneity of rare genetic diseases and is the first report elucidating the genetic profile of (consanguineous and nonconsanguineous) rare genetic diseases in the Bangladesh population.

Predicting Consumer Green Product Purchase Attitudes and Behavioral Intention During COVID-19 Pandemic.

This work has aimed to investigate the consumers' green product purchase attitudes and behavioral intention during COVID-19 pandemic. Data was collected through a survey method of 503 consumers in Malaysia. Data were analyzed using the partial least square method. The findings revealed that fear of COVID-19 pandemic has a significant impact on green product behavioral intention. Green product literacy, green product orientation, and social influence have a significant influence on green product purchase attitudes. The results also indicated that consumers' green product purchase attitudes mediate the effect of green product literacy, green product orientation, and social influence on behavioral intention. The findings of this work will provide strategically relevant references to green marketers and retail managers in the understanding of consumers' green product purchase attitudes and green product behavioral intention during the ongoing uncertainty of the COVID-19 pandemic.

Gonadal mosaicism of large terminal de novo duplication and deletion in siblings with variable intellectual disability phenotypes.

BACKGROUND: Intellectual disability (ID) is a complex condition that can impact multiple domains of development. The genetic contribution to ID's etiology is significant, with more than 100 implicated genes and loci currently identified. The majority of such variants are rare and de novo genetic mutations. METHODS: We have applied whole-genome microarray to identify large, rare, clinically relevant copy number variants (CNVs). We have applied well-established algorithms for variants call. Quantitative polymerase chain reaction (qPCR) was applied to validate the variants using three technical replicates for each family member. To assess whether the copy number variation was due to balanced translocation or mosaicism, we further conducted droplet digital PCR (ddPCR) on the whole family. We have, as well, applied "critical-exon" mapping, human developmental brain transcriptome, and a database of known associated neurodevelopmental disorder variants to identify candidate genes. RESULTS: Here we present two siblings who are both impacted by a large terminal duplication and a deletion. Whole-genome microarray revealed an 18.82 megabase (MB) duplication at terminal locus (7q34-q36.3) of chromosome 7 and a 3.90 MB deletion impacting the terminal locus (15q26.3) of chromosome 15. qPCR and ddPCR experiments confirmed the de novo origin of the variants and the co-occurrence of these two de novo events among the siblings, but their absence in both parents, implicates an unbalanced translocation that could have mal-segregated among the siblings or a possible germline mosaicism. These terminal events impact IGF1R, CNTNAP2, and DPP6, shown to be strongly associated with neurodevelopmental disorders. Detailed clinical examination of the siblings revealed the presence of both shared and distinct phenotypic features. CONCLUSIONS: This study identified two large rare terminal de novo events impacting two siblings. Further phenotypic investigation highlights that even in the presence of identical large high penetrant variants, spectrum of clinical features can be different between the siblings.

Novel mutations in actionable breast cancer genes by targeted sequencing in an ethnically homogenous cohort.

BACKGROUND: Genetic testing is becoming an essential tool for breast cancer (BC) diagnosis and treatment pathway, and particularly important for early detection and cancer prevention. The purpose of this study was to explore the diagnostic yield of targeted sequencing of the high priority BC genes. METHODS: We have utilized a cost-effective targeted sequencing approach of high priority actionable BC genes (BRCA1, BRCA2, ERBB2 and TP53) in a homogeneous patient cohort from Bangladesh (n = 52) by using tumor and blood samples. RESULTS: Blood derived targeted sequencing revealed 25.58% (11/43) clinically relevant mutations (both pathogenic and variants of uncertain significance (VUS)), with 13.95% (6/43) of samples carrying a pathogenic mutations. We have identified and validated five novel pathogenic germline mutations in this cohort, comprising of two frameshift deletions in BRCA2, and missense mutations in BRCA1, BRCA2 and ERBB2 gene respectively. Furthermore, we have identified three pathogenic mutations and a VUS within three tumor samples, including a sample carrying pathogenic mutations impacting both TP53 (c.322dupG; a novel frameshift insertion) and BRCA1 genes (c.116G > A). 22% of tissue samples had a clinically relevant TP53 mutation. Although the cohort is small, we have found pathogenic mutations to be enriched in BRCA2 (9.30%, 4/43) compare to BRCA1 (4.65%, 2/43). The frequency of germline VUS mutations found to be similar in both BRCA1 (4.65%; 2/43) and BRCA2 (4.65%; 2/43) compared to ERBB2 (2.32%; 1/43). CONCLUSIONS: This is the first genetic study of BC predisposition genes in this population, implies that genetic screening through targeted sequencing can detect clinically significant and actionable BC-relevant mutations.