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

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

A novel TRPS1 mutation in a Moroccan family with Tricho-rhino-phalangeal syndrome type III: case report.

BACKGROUND: Tricho-rhino-phalangeal syndrome (TRPS) is an autosomal dominant disorder characterized by craniofacial and skeletal malformations including short stature, thin scalp hair, sparse lateral eyebrows, pear-shaped nose and cone shaped epiphyses. This condition is caused by haploinsufficiency of the TRPS1 gene. Previous genotype-phenotype studies have correlated exon 6 missense mutations with TRPS type III, a severe form of type I with pronounced, facial characteristics, short stature and brachydactyly and differing from type II by the absence of exostoses and mental retardation. CASE PRESENTATION: We report the first case of a Moroccan family, a father and his three children, in which the diagnosis of type III TRPS was suspected based on severe clinical and radiological features. Molecular analysis of the TRPS1 gene revealed a novel missense mutation in exon 6, (p.Ala932Ser), located in the GATA-type DNA-binding zinc finger domain. CONCLUSION: Our observations in this kindred support the previous genotype-phenotype results suggesting that patients with more pronounced facial characteristics and more severe shortening of hands and feet are more likely to have mutation in exon 6 of TRPS1.

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

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

Genetic and molecular analysis of the CLDN14 gene in Moroccan family with non-syndromic hearing loss.

BACKGROUND: Hearing loss is the most prevalent human genetic sensorineural defect. Mutations in the CLDN14 gene, encoding the tight junction claudin 14 protein expressed in the inner ear, have been shown to cause non-syndromic recessive hearing loss DFNB29. AIM: We describe a Moroccan SF7 family with non-syndromic hearing loss. We performed linkage analysis in this family and sequencing to identify the mutation causing deafness. MATERIALS AND METHODS: Genetic linkage analysis, suggested the involvement of CLDN14 and KCNE1 gene in deafness in this family. Mutation screening was performed using direct sequencing of the CLDN14 and KCNE1 coding exon gene. RESULTS: Our results show the presence of c.11C>T mutation in the CLDN14 gene. Transmission analysis of this mutation in the family showed that the three affected individuals are homozygous, whereas parents and three healthy individuals are heterozygous. This mutation induces a substitution of threonine to methionine at position 4. CONCLUSION: These data show that CLDN14 gene can be i mplicated in the development of hearing loss in SF7 family; however, the pathogenicity of c.11C>T mutation remains to be determined.

Next generation sequencing identifies a pathogenic mutation of WFS1 gene in a Moroccan family with Wolfram syndrome: a case report.

BACKGROUND: Wolfram syndrome is a rare autosomal recessive neurodegenerative disorder that affects 1/200,000 to 1/1,000,000 children. It is characterized by juvenile onset diabetes, optic nerve atrophy and other systemic manifestations. Symptoms of the disease arise mostly in early childhood with a high mortality rate due to severe neurological complications. Two causative genes have been identifed in this syndrome; the classical form is caused by autosomal recessive mutations of the WFS1 gene, and a smaller portion of patients has mutations in the CIDS2 gene, which are responsible for autosomal recessive Wolfram syndrome 2. CASE PRESENTATION: We report the case of a 28-year-old Moroccan boy born from consanguineous parents referred to the department of medical genetics at the National Institute of Health in Rabat. The diagnosis of Wolfram syndrome was made based on insulin-dependent diabetes, optic nerve atrophy, sensorineural deafness, urological abnormalities and psychiatric illness. To establish the diagnosis at a molecular level, we performed next-generation sequencing in the index patient, which revealed compound heterozygous WFS1 mutations: c.1113G > A (p.Trp371Ter) and c.1223_1224insGGAACCACCTGGAGCCCTATGCCCATTT (p.Phe408fs). This second variant has never been described in patients with Wolfram syndrome. CONCLUSION: The identification of the genetic substrate in our patient confirmed the clinical diagnosis of Wolfram syndrome and allowed us to provide him an appropriate management and genetic counseling to his family.

Exome sequencing revealed a novel homozygous METTL23 gene mutation leading to familial mild intellectual disability with dysmorphic features.

BACKGROUND: Genetic factors represent a considerable part of the etiologies of intellectual disability; however, the identification of causal genetic anomaly has long been complicated by the great clinical and genetic heterogeneity of this type of disease. With advances in next-generation sequencing technologies and functional studies, the identification of genes involved in intellectual development has led to more accurate diagnostics and better understanding of the underlying biological pathways. CASE REPORT: We report on the case of two Moroccan siblings presenting mild intellectual disability with minimal dysmorphic features in which whole exome sequencing analysis revealed homozygous mutation in the METTL23 gene. Mutations in this gene have been reported to cause autosomal recessive mild intellectual disability but the association with dysmorphic features remains controversial. CONCLUSION: Hereby, we highlight the similarity of the dysmorphic traits and the characteristic facial features in patients with METTL23-related intellectual disability, suggesting the consideration of a distinct clinical entity associating mild intellectual deficiency with specific facial dysmorphy for an efficient diagnosis orientation and a better phenotype-genotype correlation in intellectual disability disorders.

Two novel homozygous missense mutations identified in the BSND gene in Moroccan patients with Bartter's syndrome.

OBJECTIVES: Hearing loss (HL) is one of the most common sensorineural disorders. In the present study, we identified two novel missense mutations in BSND gene causing Bartter syndrome type IV which is a genetic disease with an autosomal recessive transmission, characterized by hypokalaemia, metabolic alkalosis, an elevation in plasma renin activity and hyperaldosteronism as well as sensorineural deafness. METHODS: Whole-exome sequencing was performed to study the genetic causes of Hearing loss in two unrelated patients from two Moroccan families. RESULTS: The two novel homozygous mutations p.Arg8Gly (c.22C > G), p.Thr36Asn (c.107C > A) in exon 1 of BSND gene which encodes barttin were identified in 7 patients belonging to two unrelated families originated from central region of Morocco. CONCLUSION: We identified two novel missense mutations p.Arg8Gly and p.Thr36Asn in exon 1 of BSND gene; both mutations were described for the first time in Moroccan patients with Bartter syndrome type IV.

Post-mortem diagnosis of Pompe disease by exome sequencing in a Moroccan family: a case report.

BACKGROUND: Pompe disease is an autosomal recessive lysosomal storage disorder characterized by progressive myopathy with proximal muscle weakness, respiratory muscle dysfunction, and cardiomyopathy. Its prevalence ranges between 1/9000 and 1/40,000. It is caused by compound heterozygous or homozygous mutations in the GAA gene, which encodes for the lysosomal enzyme alpha-glucosidase, required for the degrading of lysosomal glycogen. CASE PRESENTATION: In this study, we report the case of a Moroccan consanguineous family with hypertrophic cardiomyopathy and sudden cardiac deaths at an early age; our patient was a 7-month-old Moroccan girl. Whole exome sequencing identified the deleterious homozygous mutation c.236_246delCCACACAGTGC (p.Pro79ArgfsX13) of GAA gene leading to a post-mortem diagnosis of Pompe disease. CONCLUSION: The identification of the genetic substrate in our patient, the daughter, confirmed the clinical diagnosis of Pompe disease and allowed us to provide appropriate genetic counseling to the family for future pregnancies.