Publications by authors named "Ilham Ratbi"

42 Publications

Molecular diagnosis of dystrophinopathies in Morocco and report of six novel mutations.

Clin Chim Acta 2020 Jul 10;506:28-32. Epub 2020 Mar 10.

Department of Medical Genetics, National Institute of Health in Rabat, BP 769 Agdal, 10 090 Rabat, Morocco.

Dystrophinopathies are the most common genetic neuromuscular disorders during childhood, with an X-linked recessive inheritance pattern. Because of clinical and genetic heterogeneity of dystrophinopathies, genetic testing of dystrophin gene at Xp21.2 is constantly evolving. Multiplex Polymerase Chain Reaction (MPCR) is used in the first line to detect common exon deletions of dystrophin gene (accounting for 65% of mutations), followed by the Multiplex Ligation-dependent Probe Amplification (MLPA) technique to reveal deletions of exons outside the usual hotspot and duplications in male and female carriers. (MLPA adds another 10-15% positive cases to MPCR). Recently, Next Generation Sequencing allows to screen for rare large and point mutations. We report here, molecular analysis results of dystrophin gene during 27 years in a large Moroccan cohort of 356 patients, using the multiplex polymerase chain reaction (MPCR) to screen for hot-spot exon deletions. First applications of whole dystrophin gene sequencing in our lab lead to the identification of six novel mutations.
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http://dx.doi.org/10.1016/j.cca.2020.03.018DOI Listing
July 2020

Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly.

Nat Commun 2019 03 12;10(1):1180. Epub 2019 Mar 12.

Centre de Recherche en Génomique des Pathologies Humaines (GENOPATH), Faculté de Médecine et de Pharmacie, Mohammed V University of Rabat, 10100, Rabat, Morocco.

A failure in optic fissure fusion during development can lead to blinding malformations of the eye. Here, we report a syndrome characterized by facial dysmorphism, colobomatous microphthalmia, ptosis and syndactyly with or without nephropathy, associated with homozygous frameshift mutations in FAT1. We show that Fat1 knockout mice and zebrafish embryos homozygous for truncating fat1a mutations exhibit completely penetrant coloboma, recapitulating the most consistent developmental defect observed in affected individuals. In human retinal pigment epithelium (RPE) cells, the primary site for the fusion of optic fissure margins, FAT1 is localized at earliest cell-cell junctions, consistent with a role in facilitating optic fissure fusion during vertebrate eye development. Our findings establish FAT1 as a gene with pleiotropic effects in human, in that frameshift mutations cause a severe multi-system disorder whereas recessive missense mutations had been previously associated with isolated glomerulotubular nephropathy.
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http://dx.doi.org/10.1038/s41467-019-08547-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414540PMC
March 2019

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

J Med Case Rep 2018 Oct 29;12(1):322. Epub 2018 Oct 29.

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

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.
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http://dx.doi.org/10.1186/s13256-018-1855-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205784PMC
October 2018

Inherited dilated cardiomyopathy in a large Moroccan family caused by LMNA mutation.

Anatol J Cardiol 2018 Jul;20(1):65-68

Research Center in Genomics of Human Pathologies (GENOPATH), Faculty of Medicine and Pharmacy, Mohammed V University in Rabat; Rabat-Morocco.

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http://dx.doi.org/10.14744/AnatolJCardiol.2018.69639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237802PMC
July 2018

Correction to: Rarely occurring mutation of ACVR1 gene in Moroccan patient with fibrodysplasia ossificans progressiva.

Clin Rheumatol 2018 03;37(3):857

Department of Medical Genetics, National Institute of Health, 27 Avenue Ibn Batouta, BP 769, 11400, Rabat, Morocco.

One of the author's name on this article was incorrectly spelled as "Renata Borcciadi". The correct spelling is "Renata Bocciardi" and is now presented correctly in this article.
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http://dx.doi.org/10.1007/s10067-017-3909-xDOI Listing
March 2018

Marfanoid habitus is a nonspecific feature of Perrault syndrome.

Clin Dysmorphol 2017 Oct;26(4):200-204

aCenter for Human Genomics, Faculty of Medicine and Pharmacy bDepartment of Endocrinology, Diabetology and Nutrition, Avicenna Hospital, Mohammed V University cDepartment of Medical Genetics, National Institute of Health, Rabat, Morocco dDivision of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, School of Biological Sciences, University of Manchester eManchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.

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.
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http://dx.doi.org/10.1097/MCD.0000000000000198DOI Listing
October 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

Exome sequencing identifies primary carnitine deficiency in a family with cardiomyopathy and sudden death.

Eur J Hum Genet 2017 06 15;25(6):783-787. Epub 2017 Mar 15.

Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Pediatric cardiomyopathy is a rare but severe disease with high morbidity and mortality. The causes are poorly understood and can only be established in one-third of cases. Recent advances in genetic technologies, specifically next-generation sequencing, now allow for the detection of genetic causes of cardiomyopathy in a systematic and unbiased manner. This is particularly important given the large clinical variability among pediatric cardiomyopathy patients and the large number of genes (>100) implicated in the disorder. We report on the performance of whole-exome sequencing in members of a consanguineous family with a history of pediatric hypertrophic cardiomyopathy and sudden cardiac death, which led to the identification of a homozygous stop variant in the SLC22A5 gene, implicated in primary carnitine deficiency, as the likely genetic cause. Targeted carnitine tandem mass spectrometry analysis in the patient revealed complete absence of plasma-free carnitine and only trace levels of total carnitine, further supporting the causality of the SLC22A5 variant. l-carnitine supplementation in the proband led to a rapid and marked clinical improvement. This case illustrates the use of exome sequencing as a systematic and unbiased diagnostic tool in pediatric cardiomyopathy, providing an efficient route to the identification of the underlying cause, which lead to appropriate treatment and prevention of premature death.
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http://dx.doi.org/10.1038/ejhg.2017.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477358PMC
June 2017

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.

Nat Genet 2017 Feb 9;49(2):249-255. Epub 2017 Jan 9.

Human Genetics and Embryology Laboratory, Institute of Medical Biology, A*STAR, Singapore.

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.
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http://dx.doi.org/10.1038/ng.3765DOI Listing
February 2017

Non lethal Raine syndrome and differential diagnosis.

Eur J Med Genet 2016 Nov 22;59(11):577-583. Epub 2016 Sep 22.

Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université Mohammed V Souissi, Rabat, Morocco; Département de Génétique Médicale, Institut National d'Hygiène, Rabat, Morocco.

Raine syndrome is a rare autosomal recessive bone dysplasia characterized by characteristic facial features with exophthalmos and generalized osteosclerosis. Amelogenesis imperfecta, hearing loss, seizures, and intracerebral calcification are apparent in some affected individuals. Originally, Raine syndrome was originally reported as a lethal syndrome. However, recently a milder phenotype, compatible with life, has been described. Biallelic variants inFAM20C, encoding aGolgi casein kinase involved in biomineralisation, have been identified in affected individuals. We report here a consanguineous Moroccan family with two affected siblingsa girl aged 18 and a boy of 15years. Clinical features, including learning disability, seizures and amelogenesis imperfecta, initially suggested a diagnosis of Kohlschutter-Tonz syndrome. However,a novel homozygous FAM20Cvariantc.676T > A, p.(Trp226Arg) was identified in the affected siblings. Our report reinforces that Raine syndrome is compatible with life, and that mild hypophosphatemia and amelogenesis imperfecta are key features of the attenuated form.
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http://dx.doi.org/10.1016/j.ejmg.2016.09.018DOI Listing
November 2016

Cytogenetic Investigation in a Group of Ten Infertile Men with Non-Obstructive Azoospermia: First Algerian 46, XX Syndrome.

Iran J Public Health 2016 Jun;45(6):739-47

Human Genome Center, Faculty of Medicine and Pharmacy, University Mohammed V, Rabat, Morocco; Department of Medical Genetics, National Institute of Health, Rabat, Morocco.

Background: In Algeria, the data on infertility and its various causes are rare. Recently, the introduction of assisted reproduction has allowed expecting that 300000 couples, which represent 7% of couples of reproductive age, face difficulty conceiving a child. Knowing that most idiopathic cases are likely to be due to chromosomal abnormalities, we aimed to investigate genetic defects by karyotype analysis in Algerian infertile men, using peripheral blood lymphocytes.

Methods: A cytogenetic study was conducted on 10 men from infertile couples by Karyotype analysis of R-banding performed by lymphocyte culture technique. Fluorescence in situ hybridization was performed and molecular abnormalities were investigated by polymerase chain reaction. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels were evaluated by immunoradiometric method.

Results: Chromosomal abnormalities were observed in 30% of the patients. We identified a homogenous Klinefelter syndrome patient with 47, XXY karyotype, a mosaic Klinefelter syndrome patient with 47, XXY/46, XY karyotype and a 46, XX male. Fluorescence in situ hybridization showed that the sex-determining region Y was translocated to the short arm of the X chromosome in patient with 46, XX chromosomal constitution and the presence of the SRY gene was confirmed by polymerase chain reaction and electrophoresis.

Conclusion: The occurrence of chromosomal abnormalities in 30% of the infertile men strongly supports the inclusion of routine cytogenetic testing for diagnostic establishment and suitable counseling for couples seeking for assisted reproduction technologies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026828PMC
June 2016

Severe early onset retinitis pigmentosa in a Moroccan patient with Heimler syndrome due to novel homozygous mutation of PEX1 gene.

Eur J Med Genet 2016 Oct 12;59(10):507-11. Epub 2016 Sep 12.

Centre de génomique humaine, Faculté de médecine et pharmacie, Mohammed V University in Rabat, 10100, Morocco; Département de génétique médicale, Institut National d'Hygiène, BP 769 Agdal, 10090 Rabat, Morocco.

Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. It is the mildest form known to date of peroxisome biogenesis disorder caused by hypomorphic mutations of PEX1 and PEX6 genes. We report on a second Moroccan family with Heimler syndrome with early onset, severe visual impairment and important phenotypic overlap with Usher syndrome. The patient carried a novel homozygous missense variant c.3140T > C (p.Leu1047Pro) of PEX1 gene. As standard biochemical screening of blood for evidence of a peroxisomal disorder did not provide a diagnosis in the individuals with HS, patients with SNHL and retinal pigmentation should have mutation analysis of PEX1 and PEX6 genes.
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http://dx.doi.org/10.1016/j.ejmg.2016.09.004DOI Listing
October 2016

NAT2 Genotypes in Moroccan Patients with Hepatotoxicity Due to Antituberculosis Drugs.

Genet Test Mol Biomarkers 2016 Nov 19;20(11):680-684. Epub 2016 Aug 19.

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

Aim: Isoniazid (INH) is the most effective drug used as a first-line tuberculosis (TB) treatment besides rifampicin, pyrazinamide, and ethambutol. It is also the most commonly associated with hepatotoxicity. Differences of toxicity induced by INH have been attributed to genetic variability of the N-acetyltransferase 2 (NAT2) gene which encodes a drug-metabolizing enzyme. The aim of this study was to characterize the acetylation profile of patients who developed hepatotoxicity after TB treatment by genotyping NAT2 polymorphisms.

Patients And Methods: This study included 42 Moroccan patients who developed hepatotoxicity after TB treatment and 163 Moroccan controls without TB. We genotyped four selected variants of the NAT2 gene (NAT2*5, NAT2*6, NAT2*7, and NAT2*14) by Sanger sequencing for patients and real-time polymerase chain reaction for controls.

Results: The majority of patients had NAT2 genotypes previously described as slow acetylators including NAT2*5/*5, NAT2*5/*6, NAT2*6/*6, and NAT2*6/*14 (78%) and none were genotyped as rapid acetylators. Controls were slow, intermediate, and rapid acetylators with frequencies of 72.39%, 21.48%, and 6.13%, respectively.

Conclusion: There were no fast acetylator genotypes found among the patients having INH-hepatotoxicity. This finding suggests that the slow acetylator phenotype may contribute to the development of TB treatment hepatotoxicity.
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http://dx.doi.org/10.1089/gtmb.2016.0060DOI Listing
November 2016

GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability.

Am J Hum Genet 2016 09 11;99(3):704-710. Epub 2016 Aug 11.

Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, viale Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy. Electronic address:

GNB5 encodes the G protein β subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision.
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http://dx.doi.org/10.1016/j.ajhg.2016.06.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010642PMC
September 2016

First application of next-generation sequencing in Moroccan breast/ovarian cancer families and report of a novel frameshift mutation of the gene.

Oncol Lett 2016 Aug 16;12(2):1192-1196. Epub 2016 Jun 16.

Department of Medical Genetics, National Institute of Health, Rabat 769, Morocco; Human Genome Center, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat 8007, Morocco.

At present, breast cancer is the most common type of cancer in females. The majority of cases are sporadic, but 5-10% are due to an inherited predisposition to develop breast and ovarian cancers, which are transmitted as an autosomal dominant form with incomplete penetrance. The beneficial effects of clinical genetic testing, including next generation sequencing (NGS) for mutations, is major; in particular, it benefits the care of patients and the counseling of relatives that are at risk of breast cancer, in order to reduce breast cancer mortality. genetic testing was performed in 15 patients with breast cancer and a family with positivity for the heterozygous c.6428C>A mutation of the gene. Informed consent was obtained from all the subjects. Genomic DNAs were extracted and the NGS for genes was performed using the Ion Torrent Personal Genome Machine (PGM) with a 316 chip. The reads were aligned with the human reference HG19 genome to elucidate variants in the and genes. Mutations detected by the PGM platform were confirmed by target direct Sanger sequencing on a second patient DNA sample. In total, 4 variants were identified in 6 families by NGS. Of these, 3 mutations had been previously reported: c.2126insA of , and c.1310_1313delAAGA and c.7235insG of . The fourth variant, c.3453delT in , has, to the best of our knowledge, never been previously reported. The present study is the first to apply NGS of the and genes to a Moroccan population, prompting additional investigation into local founder mutations and variant characteristics in the region. The variants with no clear clinical significance may present a diagnostic challenge when performing targeted resequencing. These results confirm that an NGS approach based on Ampliseq libraries and PGM sequencing is a highly efficient, speedy and high-throughput mutation detection method, which may be preferable in lower income countries.
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http://dx.doi.org/10.3892/ol.2016.4739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950805PMC
August 2016

Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6.

Am J Hum Genet 2015 Oct 17;97(4):535-45. Epub 2015 Sep 17.

Department of Medical Genetics, University of Antwerp, Antwerp 2610, Belgium. Electronic address:

Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS-affected family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define HS as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6.
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http://dx.doi.org/10.1016/j.ajhg.2015.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596894PMC
October 2015

The Bedouin mutation c.155-166del of the TBCE gene in a patient with Sanjad-Sakati syndrome of Moroccan origin.

Ann Saudi Med 2015 Mar-Apr;35(2):170-2

Ilham Ratbi, Département de Génétique Médicale,, Institut National d'Hygiène, 27, Avenue Ibn Batouta,, B.P. 769 Rabat - Morocco, T: (+212) 613 58 67 97, F: (+212) 537 77 20 67,

Sanjad-Sakati syndrome (SSS) or hypoparathyroidism-retardation-dysmorphism syndrome (HDR) is a rare autosomal recessive disorder. It is characterized by the association of congenital hypothyroidism, growth retardation, psychomotor retardation, epilepsy, dysmorphic features (microcephaly, facial, eye, and dental anomalies), and abnormalities of the extremities. The prevalence of SSS is unknown. Reported patients are were almost exclusively from the Arabian Peninsula. They are were all homozygous for the ancestral mutation c.155- 166del of the TBCE gene, also known as "the Bedouin mutation." We report on the first clinical and molecular description of a Moroccan patient with Sanjad-Sakati syndrome. He is was a carrier for the Bedouin mutation, not surprising, knowing that part of the Moroccan population has Arabian origin. This diagnosis allowed us to provide an appropriate management to the patient, to make a genetic counseling to his family, and to enrich genetic data on the Moroccan population.
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http://dx.doi.org/10.5144/0256-4947.2015.170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6074128PMC
June 2016

A novel mutation in the endothelin B receptor gene in a moroccan family with shah-waardenburg syndrome.

Mol Syndromol 2015 Feb 28;6(1):44-9. Epub 2015 Jan 28.

Département de Génétique Médicale, Institut National d'Hygiène, France ; Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université Mohammed V Souissi, France.

Waardenburg syndrome (WS) is a neurocristopathy disorder combining sensorineural deafness and pigmentary abnormalities. The presence of additional signs defines the 4 subtypes. WS type IV, also called Shah-Waardenburg syndrome (SWS), is characterized by the association with congenital aganglionic megacolon (Hirschsprung disease). To date, 3 causative genes have been related to this congenital disorder. Mutations in the EDNRB and EDN3 genes are responsible for the autosomal recessive form of SWS, whereas SOX10 mutations are inherited in an autosomal dominant manner. We report here the case of a 3-month-old Morrocan girl with WS type IV, born to consanguineous parents. The patient had 3 cousins who died in infancy with the same symptoms. Molecular analysis by Sanger sequencing revealed the presence of a novel homozygous missense mutation c.1133A>G (p.Asn378Ser) in the EDNRB gene. The proband's parents as well as the parents of the deceased cousins are heterozygous carriers of this likely pathogenic mutation. This molecular diagnosis allows us to provide genetic counseling to the family and eventually propose prenatal diagnosis to prevent recurrence of the disease in subsequent pregnancies.
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http://dx.doi.org/10.1159/000371590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369116PMC
February 2015

Clinical and molecular findings in a Moroccan patient with popliteal pterygium syndrome: a case report.

J Med Case Rep 2014 Dec 29;8:471. Epub 2014 Dec 29.

Centre de génomique humaine, Faculté de médecine et pharmacie, Université Mohammed V Souissi, Angle Avenue Allal El Fassi et Mfadel Cherkaoui, 10100 Rabat, Morocco.

Introduction: Popliteal pterygium syndrome is a congenital malformation that includes orofacial, musculoskeletal and genitourinary anomalies. It is a rare autosomal dominant disorder due to a mutation of the IRF6 gene on 1q32.2.

Case Presentation: A one-month-old Moroccan baby boy was diagnosed with typical features of popliteal pterygium syndrome and carried the c.250C>T; p.Arg84Cys mutation of the IRF6 gene.

Conclusions: We report on the first description of a Moroccan popliteal pterygium syndrome patient. This diagnosis allowed us to provide an appropriate course of management to the patient and offer genetic counseling to his family.
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http://dx.doi.org/10.1186/1752-1947-8-471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320515PMC
December 2014

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

BMC Genet 2014 Dec 29;15:156. Epub 2014 Dec 29.

Centre de génomique humaine, Faculté de médecine et de pharmacie, Université Mohammed V, Rabat, Morocco.

Background: Several 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.

Results: The 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.

Conclusion: The 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.
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http://dx.doi.org/10.1186/s12863-014-0156-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299568PMC
December 2014

Novel nonsense mutation of BRCA2 gene in a Moroccan man with familial breast cancer.

Afr Health Sci 2014 Jun;14(2):468-71

Centre de génomique humaine, Faculté de médecine et de pharmacie, Université Mohammed V Souissi, Rabat, Morocco ; Département de génétique médicale, Institut National d'Hygiène, Rabat, Morocco.

Background: Breast cancer is the most common cancer in women worldwide. About 5 to 10% of cases are due to an inherited predisposition in two major genes, BRCA1 and BRCA2, transmitted as an autosomal dominant form. Male breast cancer is rare and is mainly due to BRCA2 than BRCA1 germline mutations.

Objective: Molecular study of BRCA2 gene in man with familial breast cancer.

Methods: PCR and direct sequencing of BRCA2 gene.

Results: Identification of novel heterozygous germline mutation c.6428C>A ; p.Ser2143Stop of BRCA2 gene.
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http://dx.doi.org/10.4314/ahs.v14i2.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196389PMC
June 2014

Carrier frequency of the c.525delT mutation in the SGCG gene and estimated prevalence of limb girdle muscular dystrophy type 2C among the Moroccan population.

Genet Test Mol Biomarkers 2014 Apr 19;18(4):253-6. Epub 2014 Feb 19.

1 Département de Génétique Médicale, Institut National d'Hygiène , Rabat, Morocco .

Autosomal recessive limb-girdle muscular dystrophies (AR-LGMDs) are characterized by clinical and genetic heterogeneity. LGMD type 2C, or γ-sarcoglycanopathy, is the most frequent in North African populations as a result of the founder c.525delT mutation in the SGCG gene. Its epidemiology is poorly known in Morocco, and its prevalence among the Moroccan population has never been evaluated. This study screened 26 patients with a LGMD2C and 45 patients with an AR-LGMD phenotype for the c.525delT mutation. DNA extracted from umbilical cord blood samples of 250 newborns was tested for the same mutation. Molecular epidemiologic methods were used to calculate the frequency of heterozygotes for this mutation in Moroccan newborns and to estimate the prevalence of LGMD2C in the Moroccan population. The carrier frequency was estimated to be 1/250, which would imply that the prevalence of LGMD2C would be approximately 1/20,492 considering the effect of consanguinity. The homozygous c.525delT mutation was found in 65% of all patients with AR-LGMDs. These findings suggest that AR-LGMDs are prevalent in the Moroccan population and LGMD2C is one of the most common forms. This information might be useful for the development of diagnostic strategies on a large scale for better management of patients with AR-LGMD and genetic counseling of families.
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http://dx.doi.org/10.1089/gtmb.2013.0326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977339PMC
April 2014

Developments in FINDbase worldwide database for clinically relevant genomic variation allele frequencies.

Nucleic Acids Res 2014 Jan 14;42(Database issue):D1020-6. Epub 2013 Nov 14.

Department of Pharmacy, School of Health Sciences, University of Patras, GR-26504, Patras, Greece, Department of Computer Engineering and Informatics, Faculty of Engineering, University of Patras, GR-26504, Patras, Greece, Faculty of Medicine and Pharmacy, Human Genomic Center, University Mohammed V Souissi, 11400, Rabat, Morocco and Department of Computer and Informatics Engineering, Technological Educational Institute of Western Greece, GR-26334, Patras, Greece.

FINDbase (http://www.findbase.org) aims to document frequencies of clinically relevant genomic variations, namely causative mutations and pharmacogenomic markers, worldwide. Each database record includes the population, ethnic group or geographical region, the disorder name and the related gene, accompanied by links to any related databases and the genetic variation together with its frequency in that population. Here, we report, in addition to the regular data content updates, significant developments in FINDbase, related to data visualization and querying, data submission, interrelation with other resources and a new module for genetic disease summaries. In particular, (i) we have developed new data visualization tools that facilitate data querying and comparison among different populations, (ii) we have generated a new FINDbase module, built around Microsoft's PivotViewer (http://www.getpivot.com) software, based on Microsoft Silverlight technology (http://www.silverlight.net), that includes 259 genetic disease summaries from five populations, systematically collected from the literature representing the documented genetic makeup of these populations and (iii) the implementation of a generic data submission tool for every module currently available in FINDbase.
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http://dx.doi.org/10.1093/nar/gkt1125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964978PMC
January 2014

Marfan syndrome and cervical internal carotid artery aneurysm.

Vasa 2013 Nov;42(6):457-60

Vascular Surgery Department, Ibn Sina Hospital, Rabat, Morocco.

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http://dx.doi.org/10.1024/0301-1526/a000317DOI Listing
November 2013

A mutation in CALM1 encoding calmodulin in familial idiopathic ventricular fibrillation in childhood and adolescence.

J Am Coll Cardiol 2014 Jan 25;63(3):259-66. Epub 2013 Sep 25.

Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands. Electronic address:

Objectives: This study aimed to identify the genetic defect in a family with idiopathic ventricular fibrillation (IVF) manifesting in childhood and adolescence.

Background: Although sudden cardiac death in the young is rare, it frequently presents as the first clinical manifestation of an underlying inherited arrhythmia syndrome. Gene discovery for IVF is important as it enables the identification of individuals at risk, because except for arrhythmia, IVF does not manifest with identifiable clinical abnormalities.

Methods: Exome sequencing was carried out on 2 family members who were both successfully resuscitated from a cardiac arrest.

Results: We characterized a family presenting with a history of ventricular fibrillation (VF) and sudden death without electrocardiographic or echocardiographic abnormalities at rest. Two siblings died suddenly at the ages of 9 and 10 years, and another 2 were resuscitated from out-of-hospital cardiac arrest with documented VF at ages 10 and 16 years, respectively. Exome sequencing identified a missense mutation affecting a highly conserved residue (p.F90L) in the CALM1 gene encoding calmodulin. This mutation was also carried by 1 of the siblings who died suddenly, from whom DNA was available. The mutation was present in the mother and in another sibling, both asymptomatic but displaying a marginally prolonged QT interval during exercise.

Conclusions: We identified a mutation in CALM1 underlying IVF manifesting in childhood and adolescence. The causality of the mutation is supported by previous studies demonstrating that F90 mediates the direct interaction of CaM with target peptides. Our approach highlights the utility of exome sequencing in uncovering the genetic defect even in families with a small number of affected individuals.
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http://dx.doi.org/10.1016/j.jacc.2013.07.091DOI Listing
January 2014

[Russell Silver syndrome: report of three cases and review of the literature].

Pan Afr Med J 2013 8;14:91. Epub 2013 Mar 8.

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

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http://dx.doi.org/10.11604/pamj.2013.14.91.1645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664885PMC
September 2013

Renal amyloidosis due to familial mediterranean fever misdiagnosed.

Indian J Hum Genet 2012 Sep;18(3):363-5

Human Genomic Center, Faculty of Medicine and Pharmacy, University Mohammed V Souissi, Rabat, Morocco ; Department of Medical Genomic, National Institute of Health, Rabat, Morocco.

Familial Mediterranean fever (FMF, MIM 249100) is an autosomal recessive disease affecting mainly patients of the Mediterranean basin. It is an autoinflammatory periodic disorder characterized by recurrent episodes of fever and abdominal pain, synovitis, and pleuritis. The major complication of FMF is the development of renal AA amyloidosis. Treatment with colchicine prevents the occurrence of recurrent seizures and renal amyloidosis. The disease is caused by mutations in the MEFV gene. We report here the cases of two unrelated patients, who have been late diagnosed with FMF complicated by renal amyloidosis. We focus on the importance of early diagnosis of FMF, both to start rapidly treatment with colchicine and avoid renal amyloidosis, and to provide genetic counseling to families.
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http://dx.doi.org/10.4103/0971-6866.108043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656531PMC
September 2012

Phenotypic spectrum of Simpson-Golabi-Behmel syndrome in a series of 42 cases with a mutation in GPC3 and review of the literature.

Am J Med Genet C Semin Med Genet 2013 May 18;163C(2):92-105. Epub 2013 Apr 18.

Service de Génétique, Centre Hospitalo‐Universitaire, and UMR INSERM U930, Faculté de Médecine, Université François Rabelais, Tours, France.

Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked multiple congenital abnormality/intellectual disability syndrome characterized by pre- and post-natal overgrowth, distinctive craniofacial features, macrocephaly, variable congenital malformations, organomegaly, increased risk of tumor and mild/moderate intellectual deficiency. In 1996, Glypican 3 (GPC3) was identified as the major gene causing SGBS but the mutation detection rate was only 28-70%, suggesting either genetic heterogeneity or that some patients could have alternative diagnoses. This was particularly suggested by some reports of atypical cases with more severe prognoses. In the family reported by Golabi and Rosen, a duplication of GPC4 was recently identified, suggesting that GPC4 could be the second gene for SGBS but no point mutations within GPC4 have yet been reported. In the genetics laboratory in Tours Hospital, GPC3 molecular testing over more than a decade has detected pathogenic mutations in only 8.7% of individuals with SGBS. In addition, GPC4 mutations have not been identified thus raising the question of frequent misdiagnosis. In order to better delineate the phenotypic spectrum of SGBS caused by GPC3 mutations, and to try to define specific clinical criteria for GPC3 molecular testing, we reviewed the clinical features of all male cases with a GPC3 mutation identified in the two molecular laboratories providing this test in France (Tours and Paris). We present here the results of the analysis of 42 patients belonging to 31 families and including five fetuses and three deceased neonates.
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http://dx.doi.org/10.1002/ajmg.c.31360DOI Listing
May 2013

Exome sequencing reveals a novel Moroccan founder mutation in SLC19A3 as a new cause of early-childhood fatal Leigh syndrome.

Brain 2013 Mar 18;136(Pt 3):882-90. Epub 2013 Feb 18.

Department of Genetics and Cell Biology, P.O. Box 616, 6200 MD Maastricht, the Netherlands.

Leigh syndrome is an early onset, often fatal progressive neurodegenerative disorder caused by mutations in the mitochondrial or nuclear DNA. Until now, mutations in more than 35 genes have been reported to cause Leigh syndrome, indicating an extreme genetic heterogeneity for this disorder, but still only explaining part of the cases. The possibility of whole exome sequencing enables not only mutation detection in known candidate genes, but also the identification of new genes associated with Leigh syndrome in small families and isolated cases. Exome sequencing was combined with homozygosity mapping to identify the genetic defect in a Moroccan family with fatal Leigh syndrome in early childhood and specific magnetic resonance imaging abnormalities in the brain. We detected a homozygous nonsense mutation (c.20C>A; p.Ser7Ter) in the thiamine transporter SLC19A3. In vivo overexpression of wild-type SLC19A3 showed an increased thiamine uptake, whereas overexpression of mutant SLC19A3 did not, confirming that the mutation results in an absent or non-functional protein. Seventeen additional patients with Leigh syndrome were screened for mutations in SLC19A3 using conventional Sanger sequencing. Two unrelated patients, both from Moroccan origin and one from consanguineous parents, were homozygous for the same p.Ser7Ter mutation. One of these patients showed the same MRI abnormalities as the patients from the first family. Strikingly, patients receiving thiamine had an improved life-expectancy. One patient in the third family deteriorated upon interruption of the thiamine treatment and recovered after reinitiating. Although unrelated, all patients came from the province Al Hoceima in Northern Morocco. Based on the recombination events the mutation was estimated to have occurred 1250-1750 years ago. Our data shows that SLC19A3 is a new candidate for mutation screening in patients with Leigh syndrome, who might benefit from high doses of thiamine and/or biotin. Especially, Moroccan patients with Leigh syndrome should be tested for the c.20C>A founder mutation in SLC19A3.
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http://dx.doi.org/10.1093/brain/awt013DOI Listing
March 2013