Cytogenetic and epidemiological profile of chronic myeloid leukemia in Morocco.

Chronic myeloid leukemia (CML) is a neoplastic disease of genetic origin resulting from clonal proliferation of hematopoietic stem cells (HSCs). The reciprocal translocation t(9;22)(q34;q11) is the main chromosomal abnormality involved in this pathology, usually detected by conventional cytogenetics. This article aims to investigate the epidemiological, cytogenetic, therapeutic, and clinical characteristics of Moroccan patients with CML. This research represents the first large-scale study of CML patients in Morocco and was carried out at Institut Pasteur of Morocco. Bone marrow samples were processed for cytogenetic analysis, and karyotypes were described according to an international system of human cytogenetic nomenclature (ISCN 2016). Patients were studied according to their epidemiological characteristics, clinical information and cytogenetic results. For statistical calculations, R version 4.3.1 was used to analyze the data and calculate the statistical parameters. RStudio and Power BI were used for data visualization. The National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) method of incidence estimation was used to calculate our incidence. We received 826 patients (from 1992 to 2023) who were referred for suspected CML or who were undergoing treatment. Only 650 patients with confirmed CML were included in the study, all of whom underwent their first cytogenetic test. The median age of our patients was 45 years and the sex ratio was 1.03. At the time of diagnosis, 147 (30%) of the patients had clinical manifestations. Most patients were diagnosed in the chronic phase (94.5%). Nineteen complex variant translocations of the Philadelphia (Ph) chromosome were detected. At the time of diagnosis, 55 (11.5%) patients had ACAs, of which 30 (54.5%) were high-risk ACAs. Based on data from 174 patients treated with imatinib, the median time to complete cytogenetic response (CCyR) was 11 months, and at the last cytogenetic follow-up, 81 patients (46.6%) achieved CCyR, while 64 patients (36.8%) showed no response to treatment. Regarding adherence to European LeukemiaNet (ELN) guidelines, 58 patients (33%) were followed according to these guidelines, with optimal treatment in 8.6%, suboptimal treatment in 7% and treatment failure in 18%. The estimated incidence of chronic myeloid leukemia calculated is 0.6 cases per 100,000 in the Casablanca region. This study provides a detailed overview of CML in Morocco, highlighting important clinical, cytogenetic and therapeutic aspects despite some limitations. It also highlights the need to deepen our understanding of this complex disease for disease management in our specific context.

Impact and prevalence of comorbidities and complications on the severity of COVID-19 in association with age, gender, obesity, and pre-existing smoking: A meta-analysis.

Background: COVID-19 patients usually present multiple comorbidities and complications associated with severe forms of SARS-CoV-2 infection. This study aimed to assess the risk factors and prevalence of comorbidities and complications contributing to the severity of COVID-19. Methods: This meta-analysis was performed according to PRISMA guidelines. We searched various databases, including PubMed, Google Scholar, and Scopus (between 2020 and 2023), for eligible studies for this meta-analysis. Results: Thirty-three studies were eligible, including 85,812 patients, of which 36 % (30,634/85,812) had severe disease, whereas 64 % (55,178/85,812) had non-severe disease. Severe cases were potentially correlated with the following factors: gender (male) (odd ratio (OR) = 1.52, 95 % CI: 1.34-1.73), advanced age (OR = 3.06, 95 % CI: 2.18-4.40) pre-existing smoking (OR = 1.33, 95 % CI: 1.01-1.75), obesity (OR = 2.11, 95 % CI: 1.47-3.04), diabetes (OR = 1.81, 95 % CI: 1.35-2.43), hypertension (OR = 2.22, 95 % CI: 1.72-2.87), coronary heart disease (OR = 2.17, 95 % CI: 1.42-3.31), CKD (OR = 2.27, 95 % CI: 1.26-4.06), COPD (OR = 1.95, 95 % CI: 1.22-3.09), malignancy (OR = 1.63, 95 % CI: 1.07-2.49) and cerebrovascular disease (OR = 2.76, 95 % CI: 1.63-4.62). All these comorbidities were significantly higher in the severe COVID-19 group compared with the non-severe COVID-19 group. In addition, the most severe complications were associated with shock (OR = 28.08, 95 % CI: 3.49-226.03), ARDS (OR = 13.09, 95 % CI: 5.87-29.18), AKI (OR = 16.91, 95 % CI: 1.87-152.45) and arrhythmia (OR = 7.47, 95 % CI: 2.96-18.83). However, these complications were the most likely to prevent recovery in patients with severe affections compared with non-severe affection groups. Conclusion: All the comorbidities and complications listed above are more likely to cause severe forms of COVID-19 in some patients and hinder recovery. They are therefore risk factors to be controlled to minimize the undesirable effects of the disease.

Evaluation of SARS-CoV-2 infection risks after primary vaccination with BNT162b2, BBIBP-CorV, or ChAdOx1-nCOV-19 and after homologous and heterologous booster vaccinations with these vaccines and evaluation of SARS-CoV-2 reinfection profiles.

Background: The emergence of SARS-CoV-2 variants has significantly increased the number of cases of COVID-19 among vaccinated individuals, raising concerns about the effectiveness of current vaccines. The aim of this study was to analyze the SARS-CoV-2 infection risks after primary vaccination with BNT162b2, BBIBP-CorV, or ChAdOx1-nCOV-19 and after homologues and heterologous booster vaccinations with these vaccines, as well as the profiles of reinfected patients. Methods: We analyzed retrospectively 1082 patients vaccinated or unvaccinated with BNT162b2, BBIBP-CorV, and/or ChAdOx1nCoV-19 vaccines to determine their SARS-CoV2 infection statuses using the reverse transcription-polymerase chain reaction (RT-PCR) in addition to their clinical features. The infection risks of patients receiving the different vaccine regimens were compared using multivariate logistic regression analysis, comparing the adjusted OR of a positive COVID-19 test result. Results: Among 596 vaccinated patients, 53%(n = 286) tested positive for SARS-CoV-2 and 57%(n = 310) tested negative. Among positive cases, 10 were reinfection cases. The risk of SARS-CoV-2 infection was 1.6 (adj. OR) for patients who received one dose compared with those who received two doses (95% CI = 1.3-1.8; p < 0.01).The risk was 2.6 (adj. OR) for patients who received one dose compared with those who received three doses (95%CI = 2.1-3.3; p < 0.01), and 1.6 (adj. OR) for patients who received two doses compared with those who received three doses (95% CI = 1.3-2; p < 0.01). The patients who received two doses that were heterologous to that of the primary vaccine had the lowest risk of infection. Booster vaccinations (third dose) significantly reduced the number of positive cases with an acceptable safety profile. Higher cycle-threshold (Ct) values (indicative of viral load) were observed in vaccinated patients, whereas low Ct values were observed in unvaccinated patients. Conclusion: A complete cycle of vaccination with homologous vaccines or heterologous vaccines resulted in an acceptable reduction in SARS-CoV-2 infection. Further, vaccination was associated with a reduction in viral load.

Homozygous Missense Variants in FOXI1 and TMPRSS3 Genes Associated with Non-syndromic Deafness in Moroccan Families.

One of the most prevalent sensorineural disorders, autosomal recessive non-syndromic hearing loss (ARNSHL) which can affect all age groups, from the newborn (congenital) to the elderly (presbycusis). Important etiologic, phenotypic, and genotypic factors can cause deafness. So far, the high genetic variability that explains deafness makes molecular diagnosis challenging. In Morocco, the GJB2 gene is the primary cause of non-syndromic hereditary deafness, while the existence of a variant in the LRTOMT gene is the second cause of this condition. After excluding these two frequently occurring GJB2 and LRTOMT variants, whole-exome sequencing was carried out in two Moroccan consanguineous families with hearing loss. As a result, two novel variants in the TMPRSS3 (c.1078G>A, p. Ala 360Thr) and FOXI1 (c.6C>G, p. Ser 2Arg) genes have been discovered in deaf patients and the pathogenic effect has been anticipated by several bioinformatics and molecular modeling systems. For the first time, these variants are identified in the Moroccan population, showing the population heterogeneity and demonstrating the value of the WES in hearing loss diagnosis.

Epidemiology, clinical characteristics and risk factors of coronavirus disease 2019 (COVID-19) in Casablanca.

This is an analytical cross-sectional study of coronavirus disease 2019 (COVID-19) based on data collected between 1 November 2020 and 31 March 2021 in Casablanca focusing on the disease's epidemiological status and risk factors. A total of 4569 samples were collected and analysed by reverse-transcription polymerase chain reaction (RT-PCR); 967 patients were positive, representing a prevalence of 21.2 % for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mean age was 47.5±18 years, and infection was more common in young adults (<60 years). However, all age groups were at risk of COVID-19, and in terms of disease severity, the elderly were at greater risk because of potential underlying health problems. Among the clinical signs reported in this study, loss of taste and/or smell, fever, cough and fatigue were highly significant predictors of a positive COVID-19 test result (P<0.001). An assessment of the reported symptoms revealed that 27 % of COVID-19-positive patients (n=261) experienced loss of taste and/or smell, whereas only 2 % (n=72) of COVID-19-negative patients did (P<0.001). This result was consistent between univariate (OR=18.125) and multivariate (adjusted OR=10.484) logistic regression analyses, indicating that loss of taste and/or smell is associated with a more than 10-fold higher multivariate adjusted probability of a positive COVID-19 test (adjusted OR=10.48; P<0.001). Binary logistic regression model analysis based on clinical signs revealed that loss of taste and/or smell had a performance index of 0.846 with a P<0.001, confirming the diagnostic utility of this symptom for the prediction of COVID-19-positive status. In conclusion, symptom evaluation and a RT-PCR [taking into account cycle threshold (C t) values of the PCR proxy] test remain the most useful screening tools for diagnosing COVID-19. However, loss of taste/smell, fatigue, fever and cough remain the strongest independent predictors of a positive COVID-19 result.

Genetic heterogeneity in GJB2, COL4A3, ATP6V1B1 and EDNRB variants detected among hearing impaired families in Morocco.

BACKGROUND: Deafness is the most prevalent human sensorineural defect. It may occur as a result of an external auditory canal involvement, or a deficiency in the sound conduction mechanism, or an impairment of the cochlea, the cochlear nerve or central auditory perception. The genetic causes are the most common, as approximately 70% of hearing disorders are of hereditary origin, divided into two groups, syndromic (associated with other symptoms) and no syndromic (isolated deafness). METHODS: A whole exome sequencing was performed to identify the genetic cause of hearing loss in six Moroccan families and Sanger sequencing was used to validate mutations in these genes. THE RESULTS: The results of four out of the six families revealed four genetic variants in the genes GJB2, COL4A3, ATP6V1B1 and EDNRB responsible for non-syndromic and syndromic hearing loss. Multiple Bioinformatics programs and molecular modelling predicted the pathogenic effect of these mutations. CONCLUSIONS: We identified in Moroccan deaf patients four homozygous mutations. These results show the importance of whole exome sequencing to identify pathogenic mutations in heterogeneous disorders with multiple genes responsible.

Chromosome Abnormalities Related to Reproductive and Sexual Development Disorders: A 5-Year Retrospective Study.

Chromosomal abnormalities are the main genetic risk factor associated with reproductive and sexual development disorders (DSD). The goal of this study is to retrospectively evaluate the frequency of chromosomal aberrations in Moroccan subjects with problems of procreation or sexual ambiguity. A total of 1005 individuals, including 170 infertile couples, underwent cytogenetic analysis in the Cytogenetic Laboratory of the Pasteur Institute of Morocco. Heparinized blood samples were processed according to the standard karyotype method. A total (81.5%) of the patients studied had a normal karyotype, while the remaining (18.5%) patients had an abnormal karyotype. Female patients had more chromosomal abnormalities (52%) than male patients (48%). These chromosomal aberrations included 154 cases (83%) of sex chromosomal abnormalities, the most common being Turner's syndrome and Klinefelter's syndrome, and 31 cases (17%) had autosomal aberrations, especially chromosome 9 reversal (inv(9)(p12;q13)). The present data shows that among 170 couples, 10.6% had chromosomal abnormalities mainly involved in the occurrence of recurrent miscarriages. Genotype-phenotype correlations could not be made, and therefore, studies using more resolutive molecular biology techniques would be desirable.

A homozygous MPZL2 deletion is associated with non syndromic hearing loss in a moroccan family.

Adhesion glycoproteins are implicated in the pathophysiology of hearing loss, the most frequent inherited sensory disorder, affecting 1 in 1000 new-borns. Exome sequencing of a consanguineous Moroccan patient with mild hearing loss identified for the first time in a North African family a single homozygous mutation c.72delA in MPZL2 gene, encoding the Myelin Protein Zero-Like 2, reported as causing deafness in two other populations. Variable tandem repeat genotyping of this family revealed that the c.72delA MPZL2 allele shared a common haplotype with Turkish and Dutch families. These results confirm the pathogenicity of this MPZL2 mutation in recessive mild to moderate non-syndromic deafness.

Further Evidence for the Implication of the MET Gene in Non-Syndromic Autosomal Recessive Deafness.

Mutations in the mesenchymal epithelial transition factor (MET) gene are frequently associated with multiple human cancers but can also lead to human non-syndromic autosomal recessive deafness (DFNB97). In the present study, we identified a novel homozygous missense mutation in the METgene causing a non-syndromic hearing impairment DFNB97 form. Whole-exome sequencing was performed to determine the genetic causes of hearing loss in a Moroccan consanguineous family with an affected daughter. The structural analysis of native and mutant in the SEMA domain of the MET receptor was investigated using a molecular dynamics simulation (MDS) approach. We identified a novel pathogenic homozygous c.948A>G (p.Ile316Met) mutation in the MET gene in one deaf Moroccan young girl carrying a total bilateral non-syndromic hearing impairment. The results of the MDS approach show that an Ile316Met mutation in the SEMA domain leads to protein flexibility loss. This may produce a major impact on the structural conformation of the MET receptor, which also affects the function and binding site of the receptor. This is the first time that a mutation in the MET gene is described in a Moroccan family. Moreover, this study reports the second family in the world associating deafness and mutation in the MET gene.

Homozygous mutations in PJVK and MYO15A genes associated with non-syndromic hearing loss in Moroccan families.

OBJECTIVES: Autosomal recessive non-syndromic hearing loss is a heterogeneous disorder and the most prevalent human genetic sensorineural defect. In this study, we investigated the geneticcause of sensorineural hearing loss in Moroccan patients and presented the importance of whole exome sequencing (WES) to identify candidate genes in two Moroccan families with profound deafness. METHODS: After excluding mutations previously reported in Moroccan deaf patients, whole exome sequencing was performed and Sanger sequencing was used to validate mutations in these genes. RESULTS: Our results disclosed the c.113_114insT (p.Lys41GlufsX8) and c.406C > T (p.Arg130X) homozygous mutations in PJVK and a homozygous c.5203C > T (p.Arg1735Trp) mutation in MYO15A, both genes responsible for non-syndromic recessive hearing loss DFNB59 and DFNB3, respectively. CONCLUSION: We identified in Moroccan deaf patients two mutations in PJVK and one mutation in MYO15A described for the first time in association with non-syndromic recessive hearing loss. These results emphasize that whole exome sequencing is a powerful diagnostic strategy to identify pathogenic mutations in heterogeneous disorders with many various causative genes.

Novel compound heterozygous mutations in the GPR98 (USH2C) gene identified by whole exome sequencing in a Moroccan deaf family.

In the present work, we identified two novel compound heterozygote mutations in the GPR98 (G protein-coupled receptor 98) gene causing Usher syndrome. Whole-exome sequencing was performed to study the genetic causes of Usher syndrome in a Moroccan family with three affected siblings. We identify two novel compound heterozygote mutations (c.1054C > A, c.16544delT) in the GPR98 gene in the three affected siblings carrying post-linguale bilateral moderate hearing loss with normal vestibular functions and before installing visual disturbances. This is the first time that mutations in the GPR98 gene are described in the Moroccan deaf patients.

Novel compound heterozygous MYO7A mutations in Moroccan families with autosomal recessive non-syndromic hearing loss.

The MYO7A gene encodes a protein belonging to the unconventional myosin super family. Mutations within MYO7A can lead to either non syndromic hearing loss or to the Usher syndrome type 1B (USH1B). Here, we report the results of genetic analyses performed on Moroccan families with autosomal recessive non syndromic hearing loss that identified two families with compound heterozygous MYO7A mutations. Five mutations (c.6025delG, c.6229T>A, c.3500T>A, c.5617C>T and c.4487C>A) were identified in these families, the latter presenting two differently affected branches. Multiple bioinformatics programs and molecular modelling predicted the pathogenic effect of these mutations. In conclusion, the absence of vestibular and retinal symptom in the affected patients suggests that these families have the isolated non-syndromic hearing loss DFNB2 (nonsyndromic autosomal recessive hearing loss) presentation, instead of USH1B.

A novel PEX1 mutation in a Moroccan family with Zellweger spectrum disorders.

Mutations in the PEX1 gene are usually associated with recessive inherited diseases including Zellweger spectrum disorders. In this work, we identified a new pathogenic missense homozygous PEX1 mutation (p.Leu1026Pro, c.3077T>C) in two Moroccan syndromic deaf siblings from consanguineous parents. This variation is located in the P-loop containing nucleoside triphosphate hydrolase of protein domain and probably causes an alteration in the hydrolysis of ATP.

Update of the spectrum of GJB2 gene mutations in 152 Moroccan families with autosomal recessive nonsyndromic hearing loss.

Deafness is one of the most common genetic diseases in humans and is subject to important genetic heterogeneity. The most common cause of non syndromic hearing loss (NSHL) is mutations in the GJB2 gene. This study aims to update and evaluate the spectrum of GJB2 allele variants in 152 Moroccan multiplex families with non syndromic hearing loss. Seven different mutations were detected: c.35delG, p.V37I, p.E47X, p.G200R, p.Del120E, p.R75Q, the last three mutations were described for the first time in Moroccan deaf patients, in addition to a novel nonsense mutation, the c.385G>T which is not referenced in any database. Sixty six families (43.42%) have mutations in the coding region of GJB2, while the homozygous c.35delG mutation still to date the most represented 51/152 (33.55%). The analysis of the geographical distribution of mutations located in GJB2 gene showed more allelic heterogeneity in the north and center compared to the south of Morocco. Our results showed that the GJB2 gene is a major contributor to non syndromic hearing loss in Morocco. Thus, this report of the GJB2 mutations spectrum all over Morocco has an important implication for establishing a suitable molecular diagnosis.