Imane Cherkaoui Jaouad

Distribution of allelic and genotypic frequencies of NAT2 and CYP2E1 variants in Moroccan population

BackgroundSeveral pathogenesis and genetic factors influence predisposition to antituberculosis drug-induced hepatotoxicity (ATDH) especially for isoniazid (INH). However, the major susceptibility genes for ATDH are N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1). NAT2 gene determines the individual’s acetylator status (fast, intermediate or slow) to metabolize drugs and xenobiotics, while CYP2E1 c1/c1 genotype carriers had an increased risk of ATDH.Polymorphisms of the NAT2 and CYP2E1 genes vary remarkably among the populations of different ethnic origins.The aim of this study was to determine, for the first time, the frequency of slow acetylators in Moroccan population by genotyping of NAT2 gene variants and determining the genotype c1/c1 for CYP2E1 gene, in order to predict adverse effects of Tuberculosis treatment, particularly hepatotoxicity.ResultsThe frequencies of specific NAT2 alleles were 53%, 25%, 2% and 4% for NAT2*5, NAT2*6, NAT2*7 and NAT2*14 respectively among 163 Moroccan studied group. Genotyping of CYP2E1 gene, by real-time polymerase chain reaction using TaqMan probes, revealed frequencies of 98.5% for c1/c1 and 1.5% for c1/c2 among 130 Moroccan studied group.ConclusionThe most prevalent genotypes of NAT2 gene in Moroccans are those which encode slow acetylation phenotype (72.39%), leading to a high risk of ATDH. Most Moroccans are homozygous for c1 allele of CYP2E1 gene which aggravates hepatotoxicity in slow acetylators.This genetic background should be taken into account in determining the minimum dose of INH needed to treat Moroccan TB patients, in order to decrease adverse effects.

Cytogenetic Analysis of 5572 Patients Referred for Suspected Chromosomal Abnormalities in Morocco

OBJECTIVES The aim of this study was (1) to identify the profile of patients being referred for cytogenetic analysis in Morocco, (2) to determine the prevalence and type of chromosomal abnormalities in the different groups, (3) to compare the results with those of similar studies done in other countries. MATERIAL AND METHODS 5572 patients ranging from newborns to 50 years of age were referred to the department of medical genetics, of the Moroccan National Institute of Health between 1993 and 2010, with a variety of clinical disorders such as mental retardation; multiple congenital malformations; clinical features of Down syndrome, Turners syndrome, and Klinefelter syndrome; ambiguous sex; sterility; amenorrhea; recurrent miscarriage; and chromosome breakage syndromes. RESULTS Of the 5572 cases studied, 4068 (73%) had a normal karyotype and 1504 (27%) had chromosomal abnormalities. Various types of chromosomal anomalies were found. The most common autosomal abnormalities were Down syndrome (1095 cases) and Turners syndrome (122 cases) in abnormalities of sex chromosomes. CONCLUSION This study compares the results of cytogenetic analysis of chromosomal abnormalities in the Moroccan population with other countries and research centers. This comparison will help Moroccan clinicians to determine the priority for requesting a cytogenetic analysis in individual cases.

Further evidence for causal FAM20A mutations and first case of amelogenesis imperfecta and gingival hyperplasia syndrome in Morocco: a case report

BackgroundAmelogenesis imperfecta represents a group of developmental conditions, clinically and genetically heterogeneous, that affect the structure and clinical appearance of enamel. Amelogenesis imperfecta occurred as an isolated trait or as part of a genetic syndrome. Recently, disease-causing mutations in the FAM20A gene were identified, in families with an autosomal recessive syndrome associating amelogenesis imperfecta and gingival fibromatosis.Case presentationWe report, the first description of a Moroccan patient with amelogenesis imperfecta and gingival fibromatosis, in whom we performed Sanger sequencing of the entire coding sequence of FAM20A and identified a homozygous mutation in the FAM20A gene (c.34_35delCT), already reported in a family with this syndrome.ConclusionOur finding confirms that the mutations of FAM20A gene are causative for amelogenesis imperfecta and gingival fibromatosis and underlines the recurrent character of the c.34_35delCT in two different ethnic groups.

Low Level of Consanguinity in Moroccan Families at High Risk of Breast Cancer

BACKGROUND Breast cancer is worldwide the most common cancer in women and is a major public health problem. Genes with high or low penetrance are now clearly implicated in the onset of breast cancer, mostly the BRCA genes. All women in families at high risk of breast cancer do not develop tumours, even when they carry the familial mutation, suggesting the existence of genetic and environmental protective factors. Several studies have shown that consanguinity is linked to a decreased or an increased risk of breast cancer, but to the best of our knowledge, there is no study concerning the association between consanguinity and the occurrence of tumours in women with high risk of breast cancer. The objective of this study was to examine whether parental consanguinity in families with genetic predisposition to breast cancer affect the risk of siblings for having this cancer. MATERIALS AND METHODS Over a six-year period, 72 different patients with a histological diagnosis of breast or ovarian cancer from 42 families were recruited for genetic counselling to the Department of Medical Genetics, Rabat. Consanguinity rate was determined in cases and compared to the consanguinity rate in the Moroccan general population. RESULTS Consanguinity rates were 9.72% in patients and 15.3% in controls, but the difference was statistically not significant (p>0.001) and the mean coefficient of consanguinity was lower in breast cancer patients (0.0034) than in controls (0.0065). CONCLUSIONS Despite the relatively small sample size of the current study, our results suggest that parental consanguinity in Moroccan women might not be associated with an altered risk of breast cancer. Large scale studies should be carried out to confirm our results and to develop public health programs.

Hyaline fibromatosis syndrome with mutation c.1074delT of the CMG2 gene: a case report

IntroductionJuvenile hyaline fibromatosis and infantile systemic hyalinosis are variants of the same autosomal recessive syndrome; hyaline fibromatosis syndrome, characterized by papulonodular skin lesions, gingival hypertrophy, flexion contractures of joints, osteolytic bone lesions and stunted growth. Infantile systemic hyalinosis is distinguished from juvenile hyaline fibromatosis by its more severe phenotype, which includes hyaline deposits in multiple organs, recurrent infections and death within the first two years of life.Hyaline fibromatosis syndrome is due to mutations of the gene-encoding capillary morphogenesis protein 2 (CMG2). Cases have been reported in different countries but to the best of our knowledge, this is the first reported Moroccan patient with hyaline fibromatosis syndrome and carrying the CMG2 mutation.Case presentationWe report the case of an eight-year-old Moroccan male patient with typical features of hyaline fibromatosis syndrome: multiple recurring subcutaneous tumors, gingival hypertrophy, joint contractures and other anomalies carrying a homozygous mutation in the CMG2 gene. The identification of the mutation in our patient allowed us to do a presymptomatic diagnosis in our patient’s sister, a two-day-old newborn, who is carrying the familial mutation in the heterozygous state. Early recognition of this condition is important for genetic counseling and early treatment.ConclusionsHyaline fibromatosis syndrome might be underdiagnosed. Molecular diagnosis will help clinicians and geneticists, firstly to conduct genetic counseling, prenatal diagnosis and early treatment, and secondly to gain better understanding of the disease and genotype-phenotype correlations.

Identification of two novel SH3PXD2B gene mutations in Frank-Ter Haar syndrome by exome sequencing: Case report and review of the literature

BACKGROUND Frank-Ter Haar syndrome (FTHS) is an autosomal-recessive disorder characterized by skeletal, cardio-vascular, and eye abnormalities, such as increased intraocular pressure, prominent eyes, and hypertelorism. The most common underlying genetic defect in Frank-Ter Haar syndrome appears to be due to mutations in the SH3PXD2B gene on chromosome 5q35.1. Until now, only six mutations in SH3PXD2B gene have been identified. A genetic heterogeneity of FTHS was suggested in previous studies. DESIGN FTHS was suspected clinically in a girl of 2years old, born from non-consanguineous Moroccan healthy parents. The patient had been referred to a medical genetics outpatient clinic for dysmorphic facial features. Whole Exome Sequencing (WES) was performed in the patient and her parents, in addition to Sanger sequencing that was carried out to confirm the results. RESULTS We report the first description of a Moroccan FTHS patient with two novel compound heterozygous mutations c.806G>A; p.Trp269* (maternal allele) and c.892delC; p.Asp299Thrfs*44 (paternal allele) in the SH3PXD2B gene. Sanger sequencing confirmed this mutation in the affected girl and demonstrated that her parents carry this mutation in heterozygous state. CONCLUSION Our results confirm the clinical diagnosis of FTHS in this reported family and contribute to expand the mutational spectrum of this rare disease. Our study shows also, that exome sequencing is a powerful and a cost-effective tool for the diagnosis of a supposed genetically heterogeneous disorder such FTHS.

Novel Mutation and Structural RNA Analysis of the Noncoding RNase MRP Gene in Cartilage-Hair Hypoplasia.

Cartilage-hair hypoplasia (CHH) is an autosomal recessive disorder which is characterized by bone metaphysis anomalies with manifestations that include short stature, defective cellular immunity, and predisposition to several cancers. It is caused by mutations in RMRP, which is transcribed as an RNA component of the mitochondrial RNA-processing ribonuclease. We report the clinical and molecular data of a Moroccan patient with CHH. Sequencing of RMRP identified 2 mutations in the patient: the known mutation g.97G>A and the variation g.27G>C, which has not been reported previously. Given the high mutational heterogeneity, the high frequency of variations in the region, and the fact that RMRP is a non-coding gene, assigning the pathogenicity to RMRP mutations remains a difficult task. Therefore, we compared the characteristics of the primary and secondary structures of mutated RMRP sequences. The location of our mutations within the secondary structure of the RMRP molecule revealed that the novel g.27G>C mutation causes a disruption in the Watson-Crick base pairing, which results in an impairment of a highly conserved P3 domain. Our work prompts considering the consequences of novel RMRP nucleotide variations on conserved RNA structures to gain insights into the pathogenicity of mutations.

Surprisingly good outcome in antenatal diagnosis of severe hydrocephalus related to CCDC88C deficiency

Non-syndromic congenital hydrocephalus is aetiologically diverse and while a genetic cause is frequently suspected, it often cannot be confirmed. The most common genetic cause is L1CAM-related X-linked hydrocephalus and that explains only 5%-10% of all male cases. This underlines a current limitation in our understanding of the genetic burden of non-syndromic congenital hydrocephalus, especially for those cases with likely autosomal recessive inheritance. Additionally, the prognosis for most cases of severe congenital hydrocephalus is poor, with most of the surviving infants displaying significant intellectual impairment despite surgical intervention. It is for this reason that couples with an antenatal diagnosis of severe hydrocephalus are given the option, and may opt, for termination of the pregnancy. We present two families with CCDC88C-related recessive congenital hydrocephalus with children who had severe hydrocephalus. Those individuals who were shunted within the first few weeks of life, who did not require multiple surgical revisions, and who had a more distal truncating variant of the CCDC88C gene met their early childhood developmental milestones in some cases. This suggests that children with CCDC88C-related autosomal recessive hydrocephalus can have normal developmental outcomes under certain circumstances. We recommend CCDC88C analysis in cases of severe non-syndromic congenital hydrocephalus, especially when aqueduct stenosis with or without a medial diverticulum is seen, in order to aid prognosis discussion.

Marfanoid habitus is a nonspecific feature of Perrault syndrome

The objective of this study was to report the clinical and biological characteristics of two Perrault syndrome cases in a Moroccan family with homozygous variant c.1565C>A in the LARS2 gene and to establish genotype–phenotype correlation of patients with the same mutation by review of the literature. Whole-exome sequencing was performed. Data analysis was carried out and confirmed by Sanger sequencing and segregation. The affected siblings were diagnosed as having Perrault syndrome with sensorineural hearing loss at low frequencies; the female proband had primary amenorrhea and ovarian dysgenesis. Both affected individuals had a marfanoid habitus and no neurological features. Both patients carried the homozygous variant c.1565C>A; p.Thr522Asn in exon 13 of the LARS2 gene. This variant has already been reported as a homozygous variant in three other Perrault syndrome families. Both affected siblings of a Moroccan consanguineous family with LARS2 variants had low-frequency sensorineural hearing loss, marfanoid habitus, and primary ovarian insufficiency in the affected girl. According to the literature, this variant, c.1565C>A; p.Thr522Asn, can be correlated with low-frequency hearing loss. However, marfanoid habitus was been considered a nonspecific feature in Perrault syndrome, but we believe that it may be more specific than considered previously. This diagnosis allowed us to provide appropriate management to the patients and to provide more accurate genetic counseling to this family.