Hicham Charoute

A novel mutation in the TMC1 gene causes non-syndromic hearing loss in a Moroccan family

Autosomal recessive non-syndromic hearing loss (ARNSHL) is one of the most common genetic diseases in human and is subject to important genetic heterogeneity, rendering molecular diagnosis difficult. Whole-exome sequencing is thus a powerful strategy for this purpose. After excluding GJB2 mutation and other common mutations associated with hearing loss in Morocco, whole-exome sequencing was performed to study the genetic causes of one sibling with ARSHNL in a consanguineous Moroccan family. After filtering data and Sanger sequencing validation, one novel pathogenic homozygous mutation c.1810C>G (p.Arg604Gly) was identified in TMC1, a gene reported to cause deafness in various populations. Thus, we identified here the first mutation in the TMC1 gene in the Moroccan population causing non-syndromic hearing loss.

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

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

The Moroccan Genetic Disease Database (MGDD): a database for DNA variations related to inherited disorders and disease susceptibility

National and ethnic mutation databases provide comprehensive information about genetic variations reported in a population or an ethnic group. In this paper, we present the Moroccan Genetic Disease Database (MGDD), a catalogue of genetic data related to diseases identified in the Moroccan population. We used the PubMed, Web of Science and Google Scholar databases to identify available articles published until April 2013. The Database is designed and implemented on a three-tier model using Mysql relational database and the PHP programming language. To date, the database contains 425 mutations and 208 polymorphisms found in 301 genes and 259 diseases. Most Mendelian diseases in the Moroccan population follow autosomal recessive mode of inheritance (74.17%) and affect endocrine, nutritional and metabolic physiology. The MGDD database provides reference information for researchers, clinicians and health professionals through a user-friendly Web interface. Its content should be useful to improve researches in human molecular genetics, disease diagnoses and design of association studies. MGDD can be publicly accessed at http://mgdd.pasteur.ma.

Compound heterozygous SLC29A3 mutation causes H syndrome in a Moroccan patient: A case report

H syndrome is an autosomal recessive syndrome, which affects the skin and some vital organs, it is caused by mutations in the SLC29A3 gene, encoding the human equilibrative nucleoside transporter hENT3. This report describes a patient with typical features of H syndrome. Based on the patients clinical features, SLC29A3 was selected for molecular investigation. Through direct sequencing, a compound heterozygous alteration in the SLC29A3 gene was found. The c.243delA frameshift mutation leading to a premature termination, resulting in a truncated protein, and a splice site mutation c.300+1G>C predicted to cause a splicing error. This contribution extends the clinical variability of compound heterozygous SLC29A3 mutations resulting in an additional multisystemic manifestation of the clinical spectrum of SLC29A3 disorders.

Association analysis of APOA5 rs662799 and rs3135506 polymorphisms with obesity in Moroccan patients

The aim of the present study is to explore the association between the APOA5 polymorphisms and haplotypes with obesity in Moroccan patients. The study was performed in 459 subjects, Obese (n=164) and non-obese (n=295). All subjects were genotyped for the APOA5 -1131T>C (rs662799) and c.56C>G (rs3135506) polymorphisms. The contribution of APOA5 polymorphisms and haplotypes in the increased risk of obesity were explored using logistic regression analyses. The -1131T>C and c.56C>G polymorphisms were significantly associated with obesity. Both polymorphisms were strongly associated with increased BMI. Analysis of constructed haplotypes showed a significant association between CG haplotype and susceptibility to obesity (OR [95%CI]=3.09 [1.93-4.97]; P<0.001). These results support a potential role for APOA5 common variants and related haplotypes as risk factors for obesity.

Mediterranean Founder Mutation Database (MFMD): Taking Advantage from Founder Mutations in Genetics Diagnosis, Genetic Diversity and Migration History of the Mediterranean Population.

The Mediterranean basin has been the theater of migration crossroads followed by settlement of several societies and cultures in prehistoric and historical times, with important consequences on genetic and genomic determinisms. Here, we present the Mediterranean Founder Mutation Database (MFMD), established to offer web‐based access to founder mutation information in the Mediterranean population. Mutation data were collected from the literature and other online resources and systematically reviewed and assembled into this database. The information provided for each founder mutation includes DNA change, amino‐acid change, mutation type and mutation effect, as well as mutation frequency and coalescence time when available. Currently, the database contains 383 founder mutations found in 210 genes related to 219 diseases. We believe that MFMD will help scientists and physicians to design more rapid and less expensive genetic diagnostic tests. Moreover, the coalescence time of founder mutations gives an overview about the migration history of the Mediterranean population. MFMD can be publicly accessed from http://mfmd.pasteur.ma.

Novel variants of mitochondrial DNA associated with Type 2 diabetes mellitus in Moroccan population

Abstract In this study, we investigated the association of mtDNA variants and haplogroups with Type 2 diabetes (T2D) in Moroccan patients. The Hypervariable Segments 1 of the mtDNA was sequenced in 108 diabetic patients and 97 controls. Association analyses were performed using Fisher’s exact test and multivariate logistic regression. The prevalence of five mtDNA variants (C16187T, C16270T, T16172C, A16293G, and C16320T) was significantly higher in cases than in controls. Among these variants, only C16270T (p = .02) and C16320T (p = .03) remains significant after adjusting by age and gender. We showed that C16270T and C16320T variants were strongly associated with increased risk of T2D in Moroccan patients.

A novel mutation in SLITRK6 causes deafness and myopia in a Moroccan family

Deafness and myopia syndrome is characterized by moderate-profound, bilateral, congenital or prelingual deafness and high myopia. Autosomal recessive non-syndromic hearing loss is one of the most prevalent human genetic sensorineural defects. Myopia is by far the most common human eye disorder that is known to have a clear heritable component. The analysis of the two exons of SLITRK6 gene in a Moroccan family allowed us to identify a novel single deleterious mutation c.696delG, p.Trp232Cysfs*10 at homozygous state in the exon 2 of the SLITRK6, a gene reported to cause deafness and myopia in various populations.

A Novel Homozygous Missense Mutation in the FU-CRD2 Domain of the R-spondin1 Gene Associated with Familial 46,XX DSD

R-spondin proteins are secreted agonists of canonical WNT/β-catenin signaling. Homozygous RSPO1 mutations cause a syndrome of 46,XX disorder of sexual development (DSD), palmoplantar keratoderma (PPK), and predisposition to squamous cell carcinoma. We report exome sequencing data of two 46,XX siblings, one with testicular DSD and the other with suspected ovotesticular DSD. Both have PPK and hearing impairment and carried a novel homozygous mutation c.332G>A (p.Cys111Tyr) located in the highly conserved furin-like cysteine-rich domain-2 (FU-CRD2). Cysteines in the FU-CRDs are strictly conserved, indicating their functional importance in WNT signaling through interaction with the leucine-rich repeat-containing G-protein-coupled receptors. This is the first RSPO1 missense mutation reported in association with human disease.

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

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