Publications by authors named "Karim Ouldim"

42 Publications

Molecular and clinical assessment of maturity-onset diabetes of the young revealed low mutational rate in Moroccan families.

Int J Pediatr Adolesc Med 2022 Jun 22;9(2):98-103. Epub 2021 Mar 22.

Faculty of Sciences and Techniques, University of Sidi Mohammed Ben Abdellah, Fez, Morocco.

Background: Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance. To offer an adequate patient management and therapeutic treatment for MODY patients, in addition to an early efficient diagnosis of their asymptomatic relatives, it is crucial to set an accurate molecular diagnosis. Hence, our aim was to determine the frequency of HNF1A and GCK genes among Moroccan-suspected MODY patients.

Methods: Twenty suspected MODY patients were screened for HNF1A and GCK mutations using Sanger sequencing and MLPA methods. Segregation analysis of identified mutations was performed among family members. The pathogenic nature of missense variants was predicted using bioinformatic tools.

Results: A total of two mutations were revealed among all patients raising the diagnostic rate to 10%. We identified a large novel GCK deletion (c.209-?_1398+?del) by MLPA in one patient and a previously reported missense substitution (c.92G > A) in HNF1A gene.

Conclusion: This is the first investigation to perform the molecular diagnosis of MODY suspected patients. Our findings constitute a primary contribution towards unraveling the genetic landscape involved in the pathogenesis of MODY disease in Morocco.
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http://dx.doi.org/10.1016/j.ijpam.2021.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9152556PMC
June 2022

Molecular Diagnosis of Primary Hyperoxaluria Type 1 and Distal Renal Tubular Acidosis in Moroccan Patients With Nephrolithiasis and/or Nephrocalcinosis.

Cureus 2022 Mar 29;14(3):e23616. Epub 2022 Mar 29.

Medical Genetics and Onco-genetics Laboratory, Central Laboratory of Medical Analysis, Hospital University Hassan II, Fez, MAR.

Nephrolithiasis (NL) and urolithiasis (UL) are usual reasons for hospitalization and presentation in pediatric outpatient departments and their incidence continues to rise worldwide. In Morocco, a previous epidemiological study done in the Fez region between January 2003 and November 2013 reported a prevalence of 0.83% of childhood UL. In two studies, heritability accounted for almost half of all NL or nephrocalcinosis (NC) prevalence. Genetic factors must be considered in the etiological diagnosis of urinary lithiasis in Morocco since the frequency of consanguineous marriages is high. Hereditary tubular disorders, especially distal renal tubular acidosis (dRTA) and Dent disease, and metabolic disorders like idiopathic hypercalciuria and hyperoxaluria are the most common causes of medullary NC. Primary hyperoxaluria type 1 (PH1), which can generate an early onset of NC, and often chronic kidney disease (CKD) should always be considered and thoroughly diagnosed. The aim of this work was to establish a molecular diagnosis of PH1 and dRTA and, thus, to predict and explain the disease phenotype in a cohort of 44 Moroccan patients with NL and/or NC by analyzing the and genes that cause NL and/or NC when mutated. Disease phenotype was molecularly explained and solved in six of 44 individuals with NL and/or NC (13.6%). In the pediatric subgroup of individuals, a causative mutation in 16.2% was identified, whereas in the adult cohort no pathogenic mutation was detected. In our patients, PH1 was objectified in 67% of cases followed by dRTA in 33% of cases. We suggest that prompt detection and prophylactic treatment of UL are necessary to limit the risk of everlasting renal damage and thus prevent or delay the progression to CKD.
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http://dx.doi.org/10.7759/cureus.23616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9053370PMC
March 2022

Detection of a new deleterious gene variant in Moroccan family with inherited myoclonus-dystonia.

Clin Case Rep 2022 Mar 17;10(3):e05568. Epub 2022 Mar 17.

National Reference Laboratory Faculty of Medicine Mohammed VI University of Health Sciences (UM6SS) Casablanca Morocco.

Myoclonus-dystonia (M-D) is a pleiotropic neuropsychiatric disorder with autosomal dominant mode of inheritance with variable severity and incomplete penetrance. Pathogenic variants in ξ-sarcoglycan gene SGCE are the most frequently known genetic cause of M-D with maternal imprinting, and in most cases, a symptomatic individual inherits the pathogenic variant from his or her father. This work reported a missense mutation c.662G> T inherited in the M-D Moroccan family described for the first time, which is deleterious based on protein modeling analysis.
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http://dx.doi.org/10.1002/ccr3.5568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931306PMC
March 2022

Dietary Fat Intake and Mutations in Colorectal Cancer in a Moroccan Population.

Nutrients 2022 Jan 13;14(2). Epub 2022 Jan 13.

Laboratory of Epidemiology and Research in Health Sciences, Department of Epidemiology and Public Health, Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, Fez 30000, Morocco.

Epidemiologic data support an association between diet and mutations in the Kirsten-ras () gene involved in colorectal cancer (CRC) development. This study aimed to explore the associations between fat intake and mutations in codons 12 and 13 in cases of CRC in the Moroccan population. A multicenter case-series study nested in a large-scale Moroccan CRC case-control study was conducted. Among all CRC cases recruited, 151 specimens were available for the DNA mutation analysis. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (Cis) for mutation status according to the fat intake variables. A mutation was detected in the CRC tumor of 34.4% of the patients among whom 65.4% had a single mutation at codon 12 and 34.6% had a single mutation at codon 13. Compared to low levels of consumption, a positive association was observed between high polyunsaturated fatty acids (PUFA) consumption (>16.9 g/day) and prevalence of mutations (OR = 2.15, 95% CI = 1.01-4.59). No statistically significant associations were observed for total fat, monounsaturated fatty acids, saturated fatty acids and mutations. The results of this study suggest that PUFA may be relevant in the etiology of CRC, possibly through the generation of G > A transitions at the oncogene. Further studies are needed to verify and explain this finding.
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http://dx.doi.org/10.3390/nu14020318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8779768PMC
January 2022

Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot.

Genet Med 2021 10 10;23(10):1952-1960. Epub 2021 Jun 10.

University of Nottingham, Queen's Medical Centre, Nottingham, UK.

Purpose: Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear.

Methods: We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF.

Results: Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10).

Conclusion: Rare KDR variants, in particular PTVs, strongly associate with TOF, likely in the setting of different inheritance patterns. Supported by genetic and in vivo and in vitro functional analysis, we propose loss-of-function of VEGFR2 as one of the mechanisms involved in the pathogenesis of TOF.
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http://dx.doi.org/10.1038/s41436-021-01212-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486653PMC
October 2021

Cancer Omics in Africa: Present and Prospects.

Front Oncol 2020 14;10:606428. Epub 2020 Dec 14.

Department of Fundamental Sciences, School of Medicine, Mohammed VI University of Health Sciences, Casablanca, Morocco.

During the last century, cancer biology has been arguably one of the most investigated research fields. To gain deeper insight into cancer mechanisms, scientists have been attempting to integrate multi omics data in cancer research. Cancer genomics, transcriptomics, metabolomics, proteomics, and metagenomics are the main multi omics strategies used currently in the diagnosis, prognosis, treatment, and biomarker discovery in cancer. In this review, we describe the use of different multi omics strategies in cancer research in the African continent and discuss the main challenges facing the implementation of these approaches in African countries such as the lack of training programs in bioinformatics in general and omics strategies in particular and suggest paths to address deficiencies. As a way forward, we advocate for the establishment of an "African Cancer Genomics Consortium" to promote intracontinental collaborative projects and enhance engagement in research activities that address indigenous aspects for cancer precision medicine.
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http://dx.doi.org/10.3389/fonc.2020.606428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793679PMC
December 2020

Absence of GATA4 Mutations in Moroccan Patients with Atrial Septal Defect (ASD) Provides Further Evidence of Limited Involvement of GATA4 in Major Congenital Heart Defects.

Eurasian J Med 2020 Oct;52(3):283-287

Laboratory of Medical Genetics and Oncogenetics, HASSAN II University Hospital, Fez, Morocco.

Objective: Atrial septal defect (ASD) is one of the most common types of congenital heart disease (CHD). It is mainly caused by mutations of NK2 homeobox 5, GATA binding protein 4 (GATA4), and myosin heavy chain 6 in non-syndromic cases. This study aims to carry out, for the first time, the GATA4 mutation screening in a Moroccan population affected by ASD and compare the obtained mutation rate across populations.

Materials And Methods: A total of 33 patients were enrolled in this study. DNAs were extracted from peripheral blood samples, and we performed PCR-sequencing for GATA4 coding regions. Sequences were analyzed by sequence alignment and functional impact prediction tools. Mutation rate comparisons were performed by R software using the appropriate statistical tests.

Results: We detected 7 variants, but no pathogenic mutation was revealed, except for Asn352= that was assessed by human splicing finder algorithms to have a potential impairing effect on the splicing mechanism. Until proven by in vitro functional studies, the current pathogenic mutation rate in our cohort seems to be 0%. Statistical comparison with previous studies from all over the world shows no significant difference. Seemingly, comparison of previous GATA4 mutation rates among tetralogy of Fallot (TOF) populations shows no significant difference.

Conclusion: The low rates of GATA4 mutations observed throughout ASD and TOF international populations may suggest a limited causality of GATA4 mutations in the main CHDs, which further confirms the co-involvement of additional genetic and/or environmental factors in the manifestation of these phenotypes.
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http://dx.doi.org/10.5152/eurasianjmed.2020.19237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7651766PMC
October 2020

Associations between nutritional factors and KRAS mutations in colorectal cancer: a systematic review.

BMC Cancer 2020 Jul 28;20(1):696. Epub 2020 Jul 28.

Laboratory of Epidemiology and Research in Health Sciences, Faculty of Medicine and Pharmacy, Sidi Mohammed Ben Abdallah University, Fez, Morocco.

Background: Between 30 and 50% of colon tumors have mutations in the Kirsten-ras (KRAS) gene, which have a large nutritional attributable risk. Despite its high frequency in colorectal cancer (CRC), data to support specific associations between KRAS mutations in CRC and diet are sparse. Here, we conducted a systematic review to summarize the current epidemiological evidence on the association between various dietary factors and KRAS mutations.

Methods: PubMed, Science Direct, and Cochrane databases were searched for relevant studies published until December 31, 2019, using inclusion and exclusion criteria in accordance with PRISMA guidelines. We analyzed the studies to find associations between nutritional factors and CRC tumors with KRAS mutations in humans.

Results: We identified 28 relevant studies to include in this systematic review. In-depth analyses showed unclear associations between nutritional factors and KRAS mutations in CRC. Most epidemiological studies in the same nutrient or food often reported conflicting and/or inconclusive findings, whereas for some dietary factors, the results were homogeneous.

Conclusions: Further research using a more robust prospective cohort study is needed to lend more credence to the epidemiological associations found between KRAS mutations and dietary factors.
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http://dx.doi.org/10.1186/s12885-020-07189-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388532PMC
July 2020

Cytogenetic and FISH analysis of 93 multiple myeloma Moroccan patients.

Mol Genet Genomic Med 2020 09 23;8(9):e1363. Epub 2020 Jun 23.

Laboratory of Health and Environment, Faculty of Sciences Ain Chock, University Hassan II, Casablanca, Morocco.

Background: Multiple myeloma (MM) is a disease characterized by heterogeneous clinical presentations as well as complex genetic and molecular abnormalities. In MM, cytogenetic analysis is a challenge because of the low proliferation of malignant plasma cells. Thus, interphase fluorescence in situ hybridization (FISH), performed on sorted plasma cells detected abnormalities independently of a proliferative and infiltrative index. The purpose of this study was to explore, for the first time, the cytogenetic and molecular genetics features in Moroccan patients with multiple myeloma referred exclusively to National Reference Laboratory and to determine their risk stratification based on these features.

Methods: We performed cytogenetic analysis on 93 MM cases, all patients were subjected to FISH analysis, among which 45 patients have benefited from both FISH analysis and standard karyotype.

Results: Karyotype was normal in 78% (35/45) while, it was complex with varied structural and numerical abnormalities in 22% (10/45) of all patients, among which Hyperdiploid karyotype was found in 9% (n = 4 cases) and nonhyperdiploid in 13% (n = 6 cases). The most common numerical abnormalities were gains of chromosomes 3, 5, 9, 15, and 19. Whole chromosome losses were also frequent, affecting chromosomes X, 3, 14, 16 and 22. FISH analysis detected abnormalities in 50% of cases. The translocation t(4;14) and dup (1q) were the most frequent types of anomalies (14% and 13% respectively), followed by (17p) deletion and 14q32/IGH translocations with an undetermined origin (12% each) then the (1p) deletion (4%). For the normal karyotypes, FISH revealed chromosome abnormalities in 46%.

Conclusion: This study compares the results of cytogenetic analysis of chromosomal abnormalities in the Moroccan population with other countries. ½ patient showed at least one type of molecular genetic abnormalities. Therefore, the introducing of the cytogenetic analysis is obligatory in the diagnosis of multiple myeloma.
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http://dx.doi.org/10.1002/mgg3.1363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507047PMC
September 2020

Empowering newborn screening programs in African countries through establishment of an international collaborative effort.

J Community Genet 2020 Jul 15;11(3):253-268. Epub 2020 May 15.

American College of Medical Genetics and Genomics, Bethesda, MD, USA.

In an effort to explore new knowledge and to develop meaningful collaborations for improving child health, the First Pan African Workshop on Newborn Screening was convened in June 2019 in Rabat, Morocco. Participants included an informal network of newborn screening stakeholders from across Africa and global experts in newborn screening and sickle cell disease. Over 150 attendees, representing 20 countries, were present including 11 African countries. The agenda focused on newborn screening rationale, techniques, system development, implementation barriers, ongoing research, and collaborations both globally and across Africa. We provide an overview of the workshop and a description of the newborn screening activities in the 11 African countries represented at the workshop, with a focus on sickle cell disease.
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http://dx.doi.org/10.1007/s12687-020-00463-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295888PMC
July 2020

Analysis of Molecular Pretreated Tumor Profiles as Predictive Biomarkers of Therapeutic Response and Survival Outcomes after Neoadjuvant Therapy for Rectal Cancer in Moroccan Population.

Dis Markers 2020 11;2020:8459303. Epub 2020 Jan 11.

Laboratory of Biomedical and Translational Research, University of Medicine and Pharmacy of Fez, Morocco.

Pathologic features depending on tumor response to preoperative chemoradiotherapy are important to determine the outcomes in patients with rectal cancer. Evaluating the potential predictive roles of biomarker expression and their prognostic impact is a promising challenge. We reported here the immunohistochemical staining of a panel marker of mismatch repair protein (MMR), Ki67, HER-2, and p53. Additionally, identification of somatic mutations of KRAS, NRAS, and BRAF genes were performed by direct sequencing and pyrosequencing in pretreated biopsy tissues from 57 patients diagnosed for rectal cancer. Clinical features and pathological criteria for postneoadjuvant treatment surgical resection specimen's data were collected. Immunohistochemical expression and mutational status were correlated with therapeutic response, overall survival, and disease progression. The mean age of patients was 56 years. Seven (12.3%) out of 57 patients had a complete therapeutic response. Our analysis showed that when using complete therapeutic response (Dworak 4) and incomplete therapeutic response (Dworak 3, 2, and 1) as grouping factor, high p53 expression at the pretreatment biopsy was significantly associated to an incomplete response ( = 0.002). For 20 and 2 out of 57, KRAS and NRAS mutations were detected, respectively. The majority of these mutations affected codon 12. KRAS mutations detected at codon 146 (A146T, A146V) was associated with the appearance of recurrence and distant metastasis ( = 0.019). A high expression of HER-2 corresponding to score 3+ was observed in 3 pretreatment biopsy specimens. This class was significantly associated with a short relapse-free survival ( = 0.002). Furthermore, the high expression of Ki67 was moderately correlated with an older age ( = 0.016, = 0.319). In addition, this shows that high p53 expression in the pretreatment biopsy was associated with an incomplete response in surgical resection specimens after neoadjuvant treatment, and a HER-2 score 3+ can be a predictive factor of distant metastasis and local recurrence. Larger, prospective, and more studies are needed.
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http://dx.doi.org/10.1155/2020/8459303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977322PMC
September 2020

Implication of Microsatellite Instability Pathway in Outcome of Colon Cancer in Moroccan Population.

Dis Markers 2019 7;2019:3210710. Epub 2019 Dec 7.

Department of Pathological Anatomy, Hassan II University Hospital, Fez, Morocco.

Background: Tumors with microsatellite instability (MSI tumors) have distinct clinicopathological features. However, the relation between these tumor subtypes and survival in colon cancer remains controversial. The aim of this study was to evaluate the overall survival (OS) in patients with MSI phenotype, in FES population.

Methods: The expression of MMR proteins was evaluated by immunohistochemistry for 330 patients. , , and mutations were examined by Sanger sequencing and pyrosequencing methods. The association of MSI status with a patient's survival was assessed by the Kaplan-Meier method and log-rank test.

Results: The mean age was 54.6 years (range of 19-90 years). The MSI status was found in 11.2% of our population. MSI tumors were significantly associated with male gender, younger patients, stage I-II, right localization, and a lower rate of lymph node and distant metastasis. The OS tends to be longer in MSI tumors than MSS tumors (109.71 versus 74.08), with a difference close to significance ( = 0.05).

Conclusion: Our study demonstrates that MSI tumors have a particular clinicopathological features. The results of survival analysis indicate that the MSI status was not predictive of improved overall survival in our context with a lower statistical significance ( = 0.05) after multivariate analysis.
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http://dx.doi.org/10.1155/2019/3210710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925747PMC
May 2020

GATA4 molecular screening and assessment of environmental risk factors in a Moroccan cohort with tetralogy of Fallot.

Afr Health Sci 2018 Dec;18(4):922-930

Medico-Surgical Unit of Cardio-Pediatrics, Department of Pediatrics, HASSAN II University Hospital, Fez, Morocco.

Background: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect (CHD) with an incidence of 1/3600 live births. This disorder was associated with mutations in the transcription factors involved in cardiogenesis, like Nk2 homeobox5 (NKX2-5), GATA binding protein4 (GATA4) and T-BOX1 (TBX1). GATA4 contributes particularly to heart looping and differentiation of the second heart field.

Objectives: The aim of this study was to screen a Moroccan cohort with tetralogy of Fallot for GATA4 mutations, and to assess environmental risk factors that could be involved in the occurrence of this disorder.

Methods: Thirty-one non-syndromic TOF patients, enrolled between 5 April 2014 and 18 June 2015, were screened for GATA4 mutations using direct sequencing of GATA4 coding exons. Statistical assessment of different risk factors, which is a retrospective study, was carried out using Chi-square and Fisher's exact tests.

Results: We identified seven exonic variants in nine patients (two missense and five synonymous variants); in addition of eight intronic variants. Assessment of environmental risk factors shows significant association of maternal passive smoking with TOF in the Moroccan population.

Conclusion: The present study allowed, for the first time, the molecular and environmental characterisation of Moroccan TOF population. Our findings emphasise particularly the strong association of passive smoking with the emergence of tetralogy of Fallot.
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http://dx.doi.org/10.4314/ahs.v18i4.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354854PMC
December 2018

Molecular and presymptomatic analysis of a Moroccan Lynch syndrome family revealed a novel frameshift MLH1 germline mutation.

Turk J Gastroenterol 2018 11;29(6):701-704

Department of Medical Genetics and Oncogenetics, Centre Hospitalier Universitaire Hassan II, Fez, Morocco; Laboratory of Biomedical and Translational Research, Faculté de Médecine et de Pharmacie de Fès (FMPF), Université Sidi Mohammed Ben Abdellah (USMBA), Fez, Morocco.

Lynch syndrome (LS) is an autosomal dominant disorder characterized by an increased risk of extracolonic cancers and early age of onset. It is associated with germline mutations in the DNA mismatch repair (MMR) genes. We report a case of a patient with colorectal cancer referred to our medical genetics department for molecular analysis and genetic counseling. The proband is a 64-year-old woman diagnosed with a tumor of the cecum. Histopathological examination showed a moderately differentiated mucinous adenocarcinoma categorized by pT3 N0. Analysis of her pedigree revealed three siblings who had colon cancer, as well as one relative with brain cancer. Based on these findings, molecular genetic investigation was found to be necessary in order to identify the disease-causing mutation. Immunohistochemistry staining of MMR proteins was performed on the tumor sample of the index proband. Mutational analysis of the MLH1/MSH2 genes was carried out. Analysis was extended to the family members and the general population. This led to the identification of a heterozygous frameshift duplication in the MLH1 gene at position 910 (c.910dupG). Three siblings had inherited the mutation from their mother, two of whom were asymptomatic at the time of diagnosis. To the best of our knowledge, this is a novel pathogenic duplication that has not been reported in the databases and literature. The outcome of the present case suggests that this mutation was the primary cause of LS in the family.
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http://dx.doi.org/10.5152/tjg.2018.17761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284679PMC
November 2018

The First Molecular Screening of MLH1 and MSH2 Genes in Moroccan Colorectal Cancer Patients Shows a Relatively High Mutational Prevalence.

Genet Test Mol Biomarkers 2018 Aug 25;22(8):492-497. Epub 2018 Jul 25.

1 Department of Medical Genetics and Oncogenetics, Centre Hospitalier Hassam II , Fez, Morocco .

Introduction: Lynch syndrome (LS) is an autosomal dominant disorder characterized by early age of onset and increased risk of developing extracolonic tumors. Molecular diagnosis of LS requires identification of germline mutations in one of the Mismatch Repair (MMR) genes.

Aim: The objective of the study was to investigate the prevalence of MLH1/MSH2 mutation carriers among Moroccan patients with colorectal cancer (CRC) in a hospital-based cohort.

Methods: In this study, 214 CRC patients from COLORECFez cohort were included. Patients whose tumors showed MMR deficiency (MMR-D) and wild-type BRAF were selected to undergo mutational analysis of the MLH1 and MSH2 genes using Sanger sequencing.

Results: A total of 24 MMR-D tumors were identified (11.2%) among 214 CRC tested for MMR protein expression. The BRAF p.Val600Glu mutation was absent in all tumors deficient for MLH1 protein. Molecular screening showed germline MMR mutations (MLH1/MSH2) in four cases, two of which fulfilled Amsterdam criteria II and two met at least one of the revised Bethesda guidelines. The estimated frequency of MLH1/MSH2 mutations in Moroccan CRC patients was 1.87%.

Conclusions: The present study reports a relatively high incidence of MLH1/MSH2 (1.87%). These results confirm the contribution of MMR genes to CRC susceptibility in our population and provide evidence regarding the requirement of implementing a national screening program for LS in Morocco.
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http://dx.doi.org/10.1089/gtmb.2018.0067DOI Listing
August 2018

[Fanconi anemia at the University Hospital (CHU) Hassan II of Fez: about 6 cases].

Pan Afr Med J 2017 4;28:286. Epub 2017 Dec 4.

Faculté de Médecine et de Pharmacie de Fès, Maroc.

Fanconi anemia is a recessive disorder associated with chromosomal instability. It is marked by phenotypical heterogeneity which includes medullary deficiency, a variable malformation syndrome, a predisposition to develop acute leukaemias myéloïdes (ALM) and a cellular over-sensitiveness with the agents bridging the ADN. The diagnosis is based on the abnormal increase in the rate of spontaneous breaks chromosomal but especially and in a specific way, on a clear increase in these chromosomal breaks in the presence of bifunctional alkylating agents, which is the case in our six patients. Genetic counseling is that available for autosomal recessive diseases. We report our initial observations conducted at the University Hospital (CHU) Hassan II of Fez confirmed by the detection of a large chromosomal instability after culture with Mitomycin C compared to a normal control group. The purpose of this study was to update our knowledge of Fanconi anemia genes and to highlight the role of cytogenetics in its diagnosis and the genetic counseling for better management of affected children and their families.
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http://dx.doi.org/10.11604/pamj.2017.28.286.4372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011001PMC
July 2018

Gut microbiome of Moroccan colorectal cancer patients.

Med Microbiol Immunol 2018 Aug 23;207(3-4):211-225. Epub 2018 Apr 23.

Laboratory of Physiology, Genetics and Ethnopharmacology, Faculty of Sciences of Oujda, University Mohammed Premier, Oujda, Morocco.

Although colorectal cancer is the third leading cause of death in Morocco, there are no studies of the microbiome changes associated with the disease in the Moroccan population. The aim of our study was to compare the stool microbiome of Moroccan cancer patients with healthy individuals. We analyzed the microbiome composition of samples from 11 CRC patients and 12 healthy individuals by 16S rRNA amplicon sequencing. Principal coordinate analysis of samples revealed defined cancer versus healthy clusters. Our findings showed that cancer samples had higher proportions of Firmicutes (T = 50.5%; N = 28.4%; p = 0.04), specifically of Clostridia (T = 48.3%; N = 19.0%; p = 0.002), and Fusobacteria (T = 0.1%; N = 0.0%; p = 0.02), especially of Fusobacteriia (T = 0.1%; N = 0.0%; p = 0.02), while Bacteroidetes were enriched in healthy samples (T = 35.1%; N = 62.8%; p = 0.06), particularly the class Bacteroidia (T = 35.1%; N = 62.6%; p = 0.06). Porphyromonas, Clostridium, Ruminococcus, Selenomonas, and Fusobacterium were significantly overrepresented in diseased patients, similarly to other studies. Predicted functional information showed that bacterial motility proteins, flagellar assembly, and fatty acid biosynthesis metabolism were significantly overrepresented in cancer patients, while amino acid metabolism and glycan biosynthesis were overrepresented in controls. This suggests that involvement of these functional metagenomes is similar and relevant in the carcinogenesis process, independent of the origin of the samples. Results from this study allowed identification of bacterial taxa relevant to the Moroccan population and encourages larger studies to facilitate population-directed therapeutic approaches.
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http://dx.doi.org/10.1007/s00430-018-0542-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096775PMC
August 2018

Williams-Beuren syndrome in diverse populations.

Am J Med Genet A 2018 05;176(5):1128-1136

Human Genetics Unit, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka.

Williams-Beuren syndrome (WBS) is a common microdeletion syndrome characterized by a 1.5Mb deletion in 7q11.23. The phenotype of WBS has been well described in populations of European descent with not as much attention given to other ethnicities. In this study, individuals with WBS from diverse populations were assessed clinically and by facial analysis technology. Clinical data and images from 137 individuals with WBS were found in 19 countries with an average age of 11 years and female gender of 45%. The most common clinical phenotype elements were periorbital fullness and intellectual disability which were present in greater than 90% of our cohort. Additionally, 75% or greater of all individuals with WBS had malar flattening, long philtrum, wide mouth, and small jaw. Using facial analysis technology, we compared 286 Asian, African, Caucasian, and Latin American individuals with WBS with 286 gender and age matched controls and found that the accuracy to discriminate between WBS and controls was 0.90 when the entire cohort was evaluated concurrently. The test accuracy of the facial recognition technology increased significantly when the cohort was analyzed by specific ethnic population (P-value < 0.001 for all comparisons), with accuracies for Caucasian, African, Asian, and Latin American groups of 0.92, 0.96, 0.92, and 0.93, respectively. In summary, we present consistent clinical findings from global populations with WBS and demonstrate how facial analysis technology can support clinicians in making accurate WBS diagnoses.
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http://dx.doi.org/10.1002/ajmg.a.38672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007881PMC
May 2018

Noonan syndrome in diverse populations.

Am J Med Genet A 2017 Sep 27;173(9):2323-2334. Epub 2017 Jul 27.

Faculty of Medicine, Human Genetics Unit, University of Colombo, Colombo, Sri Lanka.

Noonan syndrome (NS) is a common genetic syndrome associated with gain of function variants in genes in the Ras/MAPK pathway. The phenotype of NS has been well characterized in populations of European descent with less attention given to other groups. In this study, individuals from diverse populations with NS were evaluated clinically and by facial analysis technology. Clinical data and images from 125 individuals with NS were obtained from 20 countries with an average age of 8 years and female composition of 46%. Individuals were grouped into categories of African descent (African), Asian, Latin American, and additional/other. Across these different population groups, NS was phenotypically similar with only 2 of 21 clinical elements showing a statistically significant difference. The most common clinical characteristics found in all population groups included widely spaced eyes and low-set ears in 80% or greater of participants, short stature in more than 70%, and pulmonary stenosis in roughly half of study individuals. Using facial analysis technology, we compared 161 Caucasian, African, Asian, and Latin American individuals with NS with 161 gender and age matched controls and found that sensitivity was equal to or greater than 94% for all groups, and specificity was equal to or greater than 90%. In summary, we present consistent clinical findings from global populations with NS and additionally demonstrate how facial analysis technology can support clinicians in making accurate NS diagnoses. This work will assist in earlier detection and in increasing recognition of NS throughout the world.
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http://dx.doi.org/10.1002/ajmg.a.38362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710841PMC
September 2017

The detection of a novel insertion mutation in exon 2 of the gene associated with familial mediterranean fever in a moroccan family.

Hum Genome Var 2017 15;4:17023. Epub 2017 Jun 15.

Medical Genetics and Oncogenetics Unit, Hassan II University Hospital, Fez, Morocco.

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease that is inherited in an autosomal recessive manner and is caused by mutations in the gene. As the name indicates, FMF occurs within families and is more common in individuals of Mediterranean descent than in persons of any other ethnicity. To date, 314 mutations have been reported. We studied a Moroccan family with a total of five members, including a mother who was presenting with symptoms of FMF, while her four children remained asymptomatic. The five patients were screened by DNA sequencing of exon 2 and exon 10 of the gene. Then, complete exome sequencing analysis of the gene was done for the patients in whom a novel mutation was detected. This analysis identified a novel single base Cytosine (C) insertion mutation in the coding region of the gene, named c.441dupC (p. Glu148Argfs*5 or E148RfsX5), which resulted in a mutated Pyrin/Marenostrin protein. This is the first report of a new mutation in exon 2 of the gene in a Moroccan family. This novel insertion mutation may provide important information for further studies of FMF pathogenesis.
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http://dx.doi.org/10.1038/hgv.2017.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494187PMC
June 2017

High frequency of the recurrent c.1310_1313delAAGA BRCA2 mutation in the North-East of Morocco and implication for hereditary breast-ovarian cancer prevention and control.

BMC Res Notes 2017 Jun 2;10(1):188. Epub 2017 Jun 2.

Centre de Génomique Humaine, Faculté de Médecine et Pharmacie, Université Mohammed V de Rabat, Rabat, Morocco.

Background: To date, a limited number of BRCA1/2 germline mutations have been reported in hereditary breast and/or ovarian cancer in the Moroccan population. Less than 20 different mutations of these two genes have been identified in Moroccan patients, and recently we reported a further BRCA2 mutation (c.1310_1313delAAGA; p.Lys437IlefsX22) in three unrelated patients, all from the North-East of the country. We aimed in this study to evaluate the frequency and geographic distribution of this BRCA2 frameshift mutation, in order to access its use as the first-line BRCA genetic testing strategy for Moroccan patients. We enrolled in this study 122 patients from different regions of Morocco, with suggestive inherited predisposition to breast and ovarian cancers. All subjects gave written informed consent to BRCA1/2 genetic testing. According to available resources of our lab and enrolled families, 51 patients were analyzed by the conventional individual exon-by-exon Sanger sequencing, 23 patients were able to benefit from a BRCA next generation sequencing and a target screening for exon 10 of BRCA2 gene was performed in 48 patients.

Results: Overall, and among the 122 patients analyzed for at least the exon 10 of the BRCA2 gene, the c.1310_1313delAAGA frameshift mutation was found in 14 patients. Genealogic investigation revealed that all carriers of this mutation shared the same geographic origin and were descendants of the North-East of Morocco.

Discussion: In this study, we highlighted that c.1310_1313delAAGA mutation of BRCA2 gene is recurrent with high frequency in patients from the North-East region of Morocco. Therefore, we propose to use, in public health strategies, the detection of this mutation as the first-line screening tests in patients with breast and ovarian cancer originated from this region.
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http://dx.doi.org/10.1186/s13104-017-2511-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457611PMC
June 2017

Novel NKX2-5 germline mutation in a Moroccan child with transitional atrio-ventricular septal defect (tAVSD).

Turk J Pediatr 2017 ;59(5):610-613

Medico-Surgical Unit of Cardio-pediatrics, Department of Pediatrics, Hassan II University Hospital, Fez, Morocco.

Atrioventricular septal defect is a complex congenital heart defects (CHD) with a prevalence of approximately 4% of all CHDs. Transitional form of atrio-ventricular septal defect (tAVSD) associates ostium primum atrial septal defect, common atrioventricular annulus with distinct atrioventricular valvar orifices in addition of restrictive ventricular septal defect. We describe in this report clinical and molecular features of a Moroccan boy that carries a novel NK2 homeobox 5 (NKX2-5) germline mutation (Pro141Ala), and exhibits a transitional atrio-ventricular septal defect. This phenotype has never been reported in association with NKX2-5 germline mutations. Pro141Ala is a non-reported pathogenic mutation that alters the nuclear localization signal sequence, leading to disruption of NKX2-5 nuclear translocation mechanism. Such alteration would decrease nuclear transcriptional activity of NKX2-5 and impair cardiogenesis process. The present report comes to widen the phenotypic spectrum of congenital heart disease caused by NKX2-5 germline mutations, and highlights as well the importance of the nuclear localization system in NKX2-5 activity.
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http://dx.doi.org/10.24953/turkjped.2017.05.019DOI Listing
January 2019

Noonan syndrome-causing genes: Molecular update and an assessment of the mutation rate.

Int J Pediatr Adolesc Med 2016 Dec 18;3(4):133-142. Epub 2016 Aug 18.

Medical Genetics and Oncogenetics Laboratory, HASSAN II University Hospital, BP 1835, Atlas, Fez 30000, Morocco.

Noonan syndrome is a common autosomal dominant disorder characterized by short stature, congenital heart disease and facial dysmorphia with an incidence of 1/1000 to 2500 live births. Up to now, several genes have been proven to be involved in the disturbance of the transduction signal through the RAS-MAP Kinase pathway and the manifestation of Noonan syndrome. The first gene described was , followed by , , , , , , and , and recently , , and , among others. Progressively, the physiopathology and molecular etiology of most signs of Noonan syndrome have been demonstrated, and inheritance patterns as well as genetic counseling have been established. In this review, we summarize the data concerning clinical features frequently observed in Noonan syndrome, and then, we describe the molecular etiology as well as the physiopathology of most Noonan syndrome-causing genes. In the second part of this review, we assess the mutational rate of Noonan syndrome-causing genes reported up to now in most screening studies. This review should give clinicians as well as geneticists a full view of the molecular aspects of Noonan syndrome and the authentic prevalence of the mutational events of its causing-genes. It will also facilitate laying the groundwork for future molecular diagnosis research, and the development of novel treatment strategies.
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http://dx.doi.org/10.1016/j.ijpam.2016.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372459PMC
December 2016

Genetics and genomic medicine in Morocco: the present hope can make the future bright.

Mol Genet Genomic Med 2016 Nov 10;4(6):588-598. Epub 2016 Nov 10.

Medical Genetics Department National Institute of Hygiene Rabat Morocco.

Genetics and genomic medicine in Morocco: the present hope can make the future bright.
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http://dx.doi.org/10.1002/mgg3.255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118203PMC
November 2016

NKX2-5 molecular screening and assessment of variant rate and risk factors of secundum atrial septal defect in a Moroccan population.

Anatol J Cardiol 2017 Mar 12;17(3):217-223. Epub 2016 Oct 12.

Medico-surgical Unit of Pediatric Cardiology, Department of Pediatrics, Hassan II University Hospital; Fez-Morocco.

Objective: Secundum atrial septal defect (ASDII) has multifactorial etiology that is combination of environmental (e.g., mother's exposure to toxicity, ethnicity) and genetic causes. Aim of the present study was to screen a Moroccan population with ASDII for NKX2-5 variants and to assess risk factors that may contribute to emergence of the disorder.

Methods: Thirty-two non-syndromic ASDII patients were screened for NKX2-5 variants using direct sequencing of polymerase chain reactionamplified coding regions. Risk factor rates were compared to general population and assessed using Fisher's exact and chi-square tests. In this retrospective study, criteria of exclusion were suggestive or confirmed syndrome association.

Results: Three heterozygous variants were detected in 4 patients. NKX2-5 variant rate in present cohort is estimated to be about 9.4%. Two prominent risk factors in the Moroccan population were highlighted: consanguinity, rate of which was significantly high at 30.8%, and previous maternal miscarriage or sibling sudden death, observed in 34.6% of cohort.

Conclusion: Impact of identified variants was discussed and possible disease-predisposing effect is suggested. Findings indicate that ASD may be favored by consanguineous marriage and that NKX2-5 variant rate in ASD patients may be affected by ethnicity. High level of maternal miscarriage and sibling sudden death suggests potential non-sporadic nature as result of putative genetic defect.
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http://dx.doi.org/10.14744/AnatolJCardiol.2016.7222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864982PMC
March 2017

[Lynch syndrome: case report and review of the literature].

Pan Afr Med J 2016 14;24:142. Epub 2016 Jun 14.

Unité de Génétique Médicale et d'Oncogénétique, Laboratoire Central d'Analyses Médicales CHU Hassan II, Fès, Maroc.

Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is the most common form of hereditary colorectal cancers. It increases cancer susceptibility, the risk of colorectal cancer in first-degree, endometrial cancer in women, and to a lesser extent, other cancers (ovarian, small bowel, stomach, urinary tract and hepatobiliary). Thus, the cumulative risk of developing colorectal cancer or endometrial cancer at the age of 80 years rises to 20 and 40% respectively. These cancers are characterized by a positive family history, their occurrence at an early age, and by the development of metachronous cancers in the same individual. This syndrome is transmitted in an autosomal dominant manner. The genes whose alteration is associated with the presence of an HNPCC belong to the family of DNA mismatch repair genes (DNA mismatch repair or MMR): MSH2, MLH1, and MSH6 are involved, in decreasing order of frequency, in 35%, 25% and 2% of cases respectively. Colonoscopic and gynecological monitoring is recommended for patients with a constitutional mutation in MSH2, MLH1 or Msh6 genes. We report one of the first moroccan case with Lynch syndrome whose constitutional mutation in the MLH1 gene was identified in a family member with colon cancer. In reply to the inquiry ofother healthy family members, a presymptomatic diagnosis was made allowing to formulate an appropriate monitoring strategy. Our study aims to highlight the role of oncogenetics in the management of patients with cancer and their families.
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http://dx.doi.org/10.11604/pamj.2016.24.142.4398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012750PMC
February 2017

Epigenetics could explain some Moroccan population colorectal cancers peculiarities: microsatellite instability pathway exploration.

Diagn Pathol 2015 Jun 24;10:77. Epub 2015 Jun 24.

Department of pathology, University hospital Hassan II of Fez, Fez, Morocco.

Background: Colorectal Cancers (CRC) are one of the most common malignancies in the world. Their incidence in Morocco, between 2005 and 2007, was 5.6 for 100000 inhabitants, which is very low compared to what found in developed countries. In addition, CRCs show a high frequency of rectal localizations, and occurs in a younger population in Morocco compared to what found in developed countries. The purpose of this study is to confirm these CRC peculiarities in Morocco and try to explain them by exploring the microsatellite instability molecular pathway.

Methods: This is a prospective observational study conducted since January 2010, including 385 patients admitted in Hassan II University Hospital of Fez. We collected clinical, radiological and pathological data. We investigated the expression of mismatch repair (MMR) proteins in 214 patients and BRAF gene mutations in 159 patients.

Results: Mean age was 55.08 +/- 15.16 years. 36.5% of patients were less than 50 years old and 49.3% of tumors were localized in the rectum. Loss of MMR protein expression was observed in 11.2% of cases. It was independently associated with individual or family history of cancer belonging to Hereditary Non-Polyposis Colorectal Cancer (HNPCC) spectrum (p = 0.01) and proximal localization (p = 0.02). No BRAF mutation was detected in all cases.

Conclusions: These results confirm the high occurrence of CRCs to young patients and the high frequency of rectal localizations in Moroccan population. They mostly show an absence of BRAF mutation, supposing a rarity of MLH1 promoter hypermethylation pathway, which may even partially explain the CRC peculiarities in our context.

Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5868184711716884.
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http://dx.doi.org/10.1186/s13000-015-0326-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477595PMC
June 2015

The first PTPN1 1 mutations in hotspot exons reported in Moroccan children with Noonan syndrome and comparison of mutation rate to previous studies.

Turk J Med Sci 2015 ;45(2):306-12

Background/aim: Noonan syndrome is an autosomal dominant disorder with an incidence of 1/1000-2500. It results from protein-tyrosine phosphatase, nonreceptor type 11 (PTPN11) mutations in roughly 50% of cases. Mutational screening of PTPN11 has been carried out in different populations. Thus, the aim of this study was to screen, for the first time, PTPN11 mutations in a series of Moroccan Noonan syndrome patients.

Materials And Methods: We used bidirectional sequencing of exons 3 and 8, considered as PTPN11 mutation hot spots, and then compared the rate of mutational events of these exons between different populations using chi-square and Fisher's exact tests.

Results: We detected 3 heterozygous mutations (Asp6lGly, Tyr63Cys, and Asn308Ser) in 4 individuals of 16 sporadic patients (25%). The rate of mutation in our cohort did not differ from that of other populations. However, we found significant differences in the mutation rate of exon 8 between one Japanese cohort and some populations, which requires more investigations to be explained.

Conclusion: The present study allowed identification of mutations clustered in exons 3 and 8 of the PTPN11 gene in a Moroccan Noonan syndrome cohort and enabled us to give appropriate genetic counseling to the mutation-positive patients.
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http://dx.doi.org/10.3906/sag-1310-50DOI Listing
July 2015

TPMT alleles in the Moroccans.

Clin Res Hepatol Gastroenterol 2015 Sep 5;39(4):e55-6. Epub 2015 Jan 5.

Laboratoire de génétique médicales et oncogénétique, laboratoire central des analyses médicales, CHU Hassan II, Fez, Morocco; Faculté de médecine et de pharmacie, université Sidi Mohamed Ben Abdellah, Fez, Morocco.

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http://dx.doi.org/10.1016/j.clinre.2014.11.002DOI Listing
September 2015
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