Publications by authors named "Laila Bouguenouch"

24 Publications

  • Page 1 of 1

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

Human cytomegalovirus and isocitrate dehydrogenase status in glioma: association and prognosis value in Moroccan population.

Germs 2022 Mar 31;12(1):32-45. Epub 2022 Mar 31.

PhD, Head of Laboratory of Human Pathology, Biomedicine and Environment, Faculty of Medicine and Pharmacy Fez, Sidi Mohammed Ben Abdellah University, Sidi Harazem Road, Fez, 30070, Morocco.

Introduction: Human cytomegalovirus (HCMV) and isocitrate dehydrogenase (IDH) have been separately associated to gliomas. IDH is a molecular marker considered in the histo-molecular classification of gliomas as well as in their management and prognosis. However, even if oncomodulatory properties were attributed to HCMV, its association to gliomas remains a controversy. Most of the studies that investigated this association used the histological classification of gliomas; nevertheless, in 2016, the World Health Organization recommended the introduction of molecular characteristics to refine this classification. The aims of this study were to determine the prevalence of HCMV in glioma patients, the association between HCMV and IDH with gliomas and subsequently their associations with survival of patients in a Moroccan cohort.

Methods: A series of 102 gliomas and 32 controls were analyzed by nested PCR (nPCR) to determine the HCMV status. PCR and sequencing were used to determine the IDH subtypes in tumors samples. IDH mutation and HCMV status were correlated to the characteristics of the tumors using SPSS, whereas the survival curves were obtained by the Kaplan-Meier method and the log rank test.

Results: HCMV shows significant association with gliomas with a detection rate of 30.4% and no case in the control group. The IDH mutation was identified in 40.9-50% of grade II-III gliomas and in 10.9% of grade IV gliomas. A significant association was obtained between survival in patients with glioblastomas and IDH/HCMV status. Glioblastoma patients with HCMV+ and IDHwt had a poor prognostic.

Conclusions: HCMV was detected exclusively in tumor cases and was significantly associated with poor prognosis in patients with gliomas and particularly with glioblastomas. The worst overall survival was significantly seen in patients with gliomas HCMV+/IDHwt. So, it will be of interest to consider HCMV and IDH status in gliomas management strategies.
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http://dx.doi.org/10.18683/germs.2022.1304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9113685PMC
March 2022

Correlation of Epidermal Growth Factor Receptor Mutation With Major Histologic Subtype of Lung Adenocarcinoma According to IASLC/ATS/ERS Classification.

Cancer Control 2022 Jan-Dec;29:10732748221084930

Faculty of Medicine and Pharmacy, Laboratory of Biomedical and Translational Research, 314397Sidi Mohamed Ben Abdellah University, Fez, Morocco.

Objective: Our prospective study aims to define the correlation of (epidermal growth factor receptor) mutations with major histological subtypes of lung adenocarcinoma from resected and non-resected specimens, according to the WHO 2015 classification, in Moroccan North East Population.

Methods: mutations of 150 primary lung adenocarcinoma were performed using Real-Time PCR or SANGER sequencing. SPSS 21 was used to assess the relationship between histological subtypes of lung adenocarcinoma and mutation status.

Results: 25 mutations were detected in the series of 150 lung adenocarcinomas, most of which were found in cases with papillary, acinar, patterns than without these patterns and more frequently occurred in the cases without solid pattern than with this pattern. A significant correlation was observed between mutation and acinar (P = 0,024), papillary pattern (P = 0,003) and, negative association with a solid pattern (P < 0,001). In females, mutations were significantly correlated with the acinar pattern (P = 0,02), whereas in males with the papillary pattern (P = 0,01). Association between the histologic component and exon 19 deletions and exon 21 mutations were also evaluated and, we found a significant correlation between the papillary major pattern with exon 19 mutations (P = 0,004) and, ex21 with the acinar component (P = 0,03).

Conclusion: An analysis of resected and non-resected lung ADC specimens in 150 Moroccan Northeast patients, revealed that acinar and papillary patterns may predict the presence of a mutation in the gene. While the solid major pattern may indicate a low mutation rate of the gene.
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http://dx.doi.org/10.1177/10732748221084930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8969502PMC
March 2022

Prognostic Impact of Tumor Budding on Moroccan Colon Cancer Patients.

Int J Surg Oncol 2022 21;2022:9334570. Epub 2022 Jan 21.

Laboratory of Anatomic and Molecular Pathology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco.

Background: Tumor budding is now emerging as one of the robust and promising histological factors that play an important role in colon cancer. In this study, we aimed to investigate the association between tumor budding and tumor clinicopathological factors, tumor molecular signature, and patient survival for the first time in a Moroccan population.

Methods: We collected data of 100 patients operated from colon adenocarcinoma. Tumor budding was assessed on HES slides, according to the International Tumor Budding Consensus Conference 2016 recommendations. The expression of MMR proteins was performed by immunohistochemistry. KRAS and NRAS mutations testing was performed by Sanger sequencing and pyrosequencing.

Results: High tumor budding grade (BUD 3) was found to be significantly associated with adverse clinicopathological features including older age (=0.03), presence of perineural invasion (=0.02), presence of vascular invasion (=0.05), distant metastases ( < 0.001), advanced TNM stage (=0.001), the occurrence of relapse (=0.04), and the high number of deceased cases (=0.02). Interestingly, we found that tumors with high-grade tumor budding were more likely to be microsatellite stable (MSS) (=0.005) and harbor more KRAS mutations (=0.02). Tumors with high-grade tumor budding were strongly associated with KRAS G12D mutation (=0.007). In all stages, high tumor budding was correlated with poorer overall survival (=0.04) and decreased relapse-free survival with a difference close to significance ((=0.09). We concluded that high tumor budding was strongly associated with unfavorable clinicopathological features and special molecular biomarkers and effectively affects the overall survival of CC patients.

Conclusions: Based on these findings and the ITBCC group recommendations, tumor budding should be taken into account along with other clinicopathologic factors in the risk assessment of colorectal cancer.
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http://dx.doi.org/10.1155/2022/9334570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8799359PMC
February 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

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

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

[Kallmann-de Morsier syndrome: about 3 cases].

Pan Afr Med J 2019 18;33:221. Epub 2019 Jul 18.

Faculté de Médecine et de Pharmacie de Fès, Université Sidi Mohamed Ben Abdellah, Fès, Maroc.

Kallmann-de Morsier syndrome (KS) is a genetic disease of the olfactory system characterized by the association of hypogonadotropic hypogonadism also referred to as gonadotropin-releasing hormone (GnRH) deficiency and anosmia or hyposmia (with hypoplasia or aplasia of the olfactory bulbs). Apart from sporadic cases that occur most often, familial Kallmann's syndrome is being described with increasing frequency. Diagnosis is mainly made in adolescents with absence of spontaneous puberty associated with smell disorders with hypoplasia or even aplasia of the bulbs and/or of the olfactory lobes on MRI. Sometimes, the diagnosis may be suspected in early childhood due to the association of cryptorchidism and micropénis. A mutation in one of known genes is only found in less than 30% of cases and, therefore, many other genes are still to be found. Hormone therapy allows pubertal growth in all cases and fertility can be obtained in most of the cases. We here report 3 cases of patients with this syndrome.
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http://dx.doi.org/10.11604/pamj.2019.33.221.11678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814956PMC
November 2019

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

Helicobacter pylori CagA EPIYA-C motifs and gastric diseases in Moroccan patients.

Infect Genet Evol 2018 12 19;66:120-129. Epub 2018 Sep 19.

Laboratoire de Microbiologie et Biologie Moléculaire, Equipe micro-organismes génomique et facteurs oncogènes, Faculté de Médecine et de Pharmacie de Fès (FMPF), Université Sidi Mohammed Ben Abdellah (USMBA), Morocco; Laboratoire de Pathologie Humaine, Biomédecine et Environnement, FMPF, USMBA, Morocco. Electronic address:

Background: The pathogenicity of cagA-positive H. pylori strains is associated with the number and type of repeated sequences named EPIYA located in the C-terminal region of the CagA protein. The aim of this study is to determine the polymorphism of the H. pylori cagA 3' region circulating in Morocco and its association with different gastric pathologies.

Methods: A total of 1353 consenting patients, were recruited in this study. The gastric biopsies performed during endoscopy were used for histological examination and for molecular characterization of H. pylori. The study of the type and number of "EPIYA" motif was identified by PCR directly on H. pylori positive biopsies.

Results: Of all the biopsies, the infection rate was 61.1%. The cagA gene was amplified in 68.9% of the cases and the analysis of the 3' region of cagA showed the exclusive presence of the "Western CagA" type with a predominance of the EPIYA-ABC motif (71.4%). The number of EPIYA-C motif varies from 0 to 2. The multinomial analysis shows that the infection with strains of H. pylori having two EPIYA-C motifs is a factor that increases the risk of developing gastric cancer compared to gastritis cases with strains lacking this motif (OR = 11.64; CI: 3.34-45.15), whereas this risk is 6 fold higher in comparison with duodenal ulcer cases (OR = 6, CI: 1.29-27.76).

Conclusions: The results of this study suggest that the number of EPIYA-C motifs might be useful as a predictive marker of the infection evolution and will help in the identification of patients at high risk of developing gastric cancer.
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http://dx.doi.org/10.1016/j.meegid.2018.09.015DOI Listing
December 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

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

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

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

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

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

[Chromosome markers: case report].

Pan Afr Med J 2013 18;15:104. Epub 2013 Jul 18.

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

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http://dx.doi.org/10.11604/pamj.2013.15.104.1993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828057PMC
December 2014

[The Cri du Chat syndrome: report of an observation].

Pan Afr Med J 2012 12;11. Epub 2012 Jan 12.

Unité de Génétique Médicale et d'oncogénétique, Laboratoire centrale d'analyses Médicales, CHU Hassan II, Fès Maroc.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3283019PMC
June 2012

[Microdeletion syndromes (Williams syndrome and deletion syndrome 22q11) at CHU Hassan II of Fez: report of 3 observations].

Pan Afr Med J 2012 12;11. Epub 2012 Jan 12.

Unité de Génétique Médicale et d'oncogénétique, Laboratoire centrale d'analyses Médicales, CHU Hassan II, Fès, Maroc.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3283021PMC
June 2012
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