Misdiagnosis of Tracher-Collins Syndrome Initially Attributed to Drug Teratogenicity: A Moroccan Case Report.

Background: Treacher Collins syndrome (TCS) is a rare congenital disorder of craniofacial development characterized by numerous developmental anomalies that are restricted to the head and neck. Most TCS cases are inherited in an autosomal dominant manner. The diagnosis of TCS relies on clinical and radiographic findings. The four genes involved in TCS are TCOF1, POLR1D, POLR1C, and POLR1B. Case presentation: In this report, we present the case of a 7-year-old Moroccan boy who exhibited distinctive dysmorphic features, including coloboma and zygomatic bone hypoplasia. Upon genetic analysis, a mutation in the TCOF1 gene was identified, conclusively confirming the presence of Treacher Collins Syndrome. It is worthy that the correct etiological diagnosis was significantly delayed due to the initial misperception that the observed malformation syndrome was a result of drug teratogenicity. Conclusions: This case highlights the importance of seeking pharmacovigilance advice if any adverse event occurs following medication use. Furthermore, requesting a genetic consultation to establish a confirmed etiological diagnosis for any malformation syndrome can significantly reduce the protracted social and psychological suffering that patients and their families may endure.

Ankyloblepharon-ectodermal Defects-cleft Lip-palate Syndrome Due to a Novel Missense Mutation in the SAM Domain of the TP63 Gene.

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a rare genetic disease with an autosomal dominant transmission, characterized by several congenital anomalies. Clinical features include ectodermal defects affecting the skin, hair, teeth, nails and sweat glands, associated with typical eyelid fusion in addition to a cleft lip and/or palate. The diagnosis is based on clinical criteria and molecular genetic testing of TP63 gene, the gene related to AEC syndrome. In this context, most reported mutations induce an amino acid change in the sterile alpha motif (SAM) domain, and are predicted to disrupt protein-protein interactions. We here describe the case of a 2-year-old Moroccan girl diagnosed with AEC syndrome on the basis of clinical features. The molecular studies and bioinformatics tools revealed a novel heterozygous missense mutation c.1798G>C (p.Gly600Arg) in exon 14 of the TP63 gene, that was not found in her parents. The molecular analysis and the early diagnosis of this syndrome are important to offer appropriate genetic counseling and management to patients and their families.

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.

Clinical and molecular report of c.1331 + 1G > A mutation of the AAAS gene in a Moroccan family with Allgrove syndrome: a case report.

BACKGROUND: Allgrove syndrome is a rare autosomal recessive disorder characterized by the triad of achalasia, alacrimia and adrenal insufficiency. It is caused by the mutations of the AAAS gene located on chromosome 12q13. The c.1331 + 1G > A mutation is one of the most common described in North Africa including Tunisia, Algeria and Libya. We report here the clinical and genetic profile of a Moroccan family with Allgrove syndrome. CASE PRESENTATION: A Moroccan sister and brother born to consanguineous parents were found, at the ages of twelve and fifteen months old respectively, to have alacrimia and isolated glucocorticoid deficiency. Later, they developed achalasia whereupon Allgrove syndrome was diagnosed clinically and confirmed by DNA sequencing which revealed a c.1331 + 1G > A mutation in the AAAS gene. CONCLUSION: This finding reinforces previous studies in demonstrating the geographic expansion of the ancestral mutation c.1331 + 1G > A in North African patients and thus enabling targeted genetic counseling. To the best of our knowledge, this is the first report of the AAAS gene mutation in Moroccan patients.

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.

Clinical and molecular findings in a Moroccan family with Jervell and Lange-Nielsen syndrome: a case report.

BACKGROUND: Jervell and Lange-Nielsen syndrome (Online Mendelian Inheritance in Man 220400) is a rare autosomal recessive cardioauditory ion channel disorder that affects 1/200,000 to 1/1,000,000 children. It is characterized by congenital profound bilateral sensorineural hearing loss, a long QT interval, ventricular tachyarrhythmias, and episodes of torsade de pointes on an electrocardiogram. Cardiac symptoms arise mostly in early childhood and consist of syncopal episodes during periods of stress, exercise, or fright and are associated with a high risk of sudden cardiac death. Jervell and Lange-Nielsen syndrome is caused by homozygous or compound heterozygous mutations in KCNQ1 on 11p15.5 or KCNE1 on 1q22.1-q22.2. CASE PRESENTATION: We report the case of a 10-year-old Moroccan boy with congenital hearing loss and severely prolonged QT interval who presented with multiple episodes of syncope. His parents are first-degree cousins. We performed Sanger sequencing and identified a homozygous variant in KCNQ1 (c.1343dupC, p.Glu449Argfs*14). CONCLUSIONS: The identification of the genetic substrate in this patient confirmed the clinical diagnosis of Jervell and Lange-Nielsen syndrome and allowed us to provide him with appropriate management and genetic counseling to his family. In addition, this finding contributes to our understanding of genetic disease in the Moroccan population.

CALR gene mutational profile in myeloproliferative neoplasms with non-mutated JAK2 in Moroccan patients: A case series and germline in-frame deletion.

BACKGROUND: The discovery of somatic mutations within the gene encoding calreticulin (CALR) in 2013 represented a major milestone in the molecular diagnosis of BCR-ABL negative myeloproliferative neoplasms (MPN). In fact, exome sequencing revealed that most patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF) lacking JAK2 or MPL mutations, harbor somatic insertion and/or deletion in exon 9 of CALR gene. In this study, we identified the first CALR gene mutational landscape in Moroccan patients with MPN nonmutated for the JAK2 gene. METHODS: We performed Sanger sequencing of exon 9 of CALR gene in blood samples obtained from 33 Moroccan patients with ET or PMF non-mutated for JAK2. RESULTS: Of the 33 patients analyzed, we detected eight distinct variants in 15 patients (45.4%); six indel mutations, five with type 1 recurrent 52bp deletion, four with type 2 recurrent 5bp insertion and one in frame deletion which was found to be a germline variant suggesting a very rare condition in MPN. CONCLUSION: This is the first cohort reported in CALR gene mutation analysis in Morocco. Our results were concordant with studies reported up to date and very encouraging in promoting the molecular diagnosis of myeloproliferative neoplasms in Moroccan patients. Moreover, the presence of a germline in frame deletion in a symptomatic patient should undermine the effectiveness of sizing assays without DNA sequencing in the diagnosis of CALR mutations.

Clinical and molecular findings in three Moroccan families with distal renal tubular acidosis and deafness: Report of a novel mutation of ATP6V1B1 gene.

BACKGROUND: Primary distal renal tubular acidosis (dRTA) is a rare genetic condition characterized by an impaired acid excretion by the intercalated cells in the renal collecting duct. Recessive forms of this disease are caused by mutations in tow major genes: ATP6V1B1 and ATP6V0A4. Causal mutations in ATP6V1B1 gene are classically associated with early sensorineural hearing loss, however cases of tubular acidosis with early deafness have also been described in patients with mutations in the ATP6V0A4 gene. METHODS: The phenotype and genotype of three Moroccan consanguineous families with dRTA and deafness were assessed. Molecular analysis was performed by PCR amplification and direct sequencing of exon 12 of ATP6V1B1 gene. RESULTS: A novel c.1169dupC frameshift mutation of ATP6V1B1 gene was identified in one family and the c.1155dupC North African mutation in the tow other families. DISCUSSION AND CONCLUSION: In this report, we propose first line genetic testing based on screening of these two mutations both located in exon 12 of ATP6V1B1 gene in Moroccan patients with recessive form of dRTA associated to precocious hearing loss. Molecular diagnosis of dRTA leads to appropriate treatment and prevention of renal failure in affected individuals and to provide genetic counseling for families at risk.

Acromelic frontonasal dysostosis and ZSWIM6 mutation: phenotypic spectrum and mosaicism.

Acromelic frontonasal dysostosis (AFND) is a distinctive and rare frontonasal malformation that presents in combination with brain and limb abnormalities. A single recurrent heterozygous missense substitution in ZSWIM6, encoding a protein of unknown function, was previously shown to underlie this disorder in four unrelated cases. Here we describe four additional individuals from three families, comprising two sporadic subjects (one of whom had no limb malformation) and a mildly affected female with a severely affected son. In the latter family we demonstrate parental mosaicism through deep sequencing of DNA isolated from a variety of tissues, which each contain different levels of mutation. This has important implications for genetic counselling.

Clinical and molecular report of novel GALC mutations in Moroccan patient with Krabbe disease: case report.

BACKGROUND: Krabbe disease (KD) or globoid cell leukodystrophy is an autosomal recessive lysosomal disorder, which affects metabolic and neurologic systems. This pathology has different forms. Infantile onset is about 85% to 90% of individuals with Krabbe disease. Disorder's onset is characterized, in early childhood, by hyperirritability, psychomotor deterioration associated to episodes of fever. To date, all reported cases have been attributed to mutations in galactosylceramidase gene (GALC gene) that encodes an enzyme which degrades galactosyl-sphingolipids (galactosylceramide, psychosine), essential in myelin production. A child compounded with two new mutations in the GALC gene was detected. CASE PRESENTATION: An eleven month old male child of Moroccan origin presented to our genetic consultation with severe symptoms that included hypotonia, fever, vision loss and feeding difficulties. He was suffering from the 4th month of life. Krabbe disease was suspected. Galactocerebrosidase deficiency was confirmed by biochemical analysis. DNA sequencing revealed a novel heterozygous compound mutation in GALC gene. The child was compounded with two mutations c.860G > A; p.Cys287Tyr and c.1622G > A; p.Trp541*. CONCLUSION: These new mutations could affect GALC structure and therefore its function. The identification of these mutations and their associated phenotypes are important to predict the prognosis and to confer to families an adequate genetic counseling.

Maternal Hypomethylation of KvDMR in a Monozygotic Male Twin Pair Discordant for Beckwith-Wiedemann Syndrome.

Beckwith-Wiedemann syndrome (BWS; OMIM 130650) is a heterogeneous overgrowth syndrome characterized by visceromegaly, macroglossia, tumor predisposition, and other congenital abnormalities. BWS is usually associated with abnormalities of chromosome 11p15, including (epi)genetic changes, paternal disomy and point mutations. A number of identical twin pairs, mostly female, have been reported to be clinically discordant for BWS. Studies of monozygotic twins discordant for BWS provide more information about failure in the DNA methylation maintenance machinery during very early embryonic development. Here, we report a case of monozygotic male twins discordant for BWS phenotype. Methylation analysis of the 2 imprinted domains at 11p15.5 (H19DMR and KvDMR) was performed by methylation-specific MLPA and pyrosequencing of DNA extracted from peripheral blood and buccal swabs of both twins. Hypomethylation at KvDMR was identified in both cell types of the affected twin, whereas his healthy brother presented hypomethylation only in blood cells and a normal methylation profile in buccal swab. For diagnostic purposes, it is important to remember that twins can share fetal circulation and possibly share hematopoietic stem cells early in development; therefore, the affected and unaffected twins can share an epigenotype that will resemble partial hypomethylation. If a patient is a twin, it is valuable to obtain a sample from a tissue other than blood.

Inhabitual autosomal recessive form of dentin dysplasia type I in a large consanguineous Moroccan family.

Dentin dysplasia is a rare autosomal dominant genetic disease characterized by defect of dentin development and the causal gene is DSPP (Dentin Sialophosphoprotein gene). We report in the present study a large Moroccan family in which dentin dysplasia is clearly transmitted as an autosomal recessive trait. Four males and females family members born from healthy consanguineous parents are carriers of the typical features of the dentin dysplasia type I. Polymorphic markers that span the DSPP gene, allowed us to show that this locus is not linked to dentin dysplasia in our family. We also excluded in our family the SMOC2 gene (Sparc Related Modular Calcium Binding Protein 2) which was recently identified as a causal gene in dentin dysplasia type I with microdontia and misshapen teeth. This family represents, a new description of autosomal recessive pattern of inheritance of dentin dysplasia type I. Moreover, this form of dentin dysplasia is not allelic to the autosomal dominant dentin dysplasia and the genetic cause is to be discovered.

Report of the First Clinical Case of a Moroccan Kabuki Patient with a Novel MLL2 Mutation.

Kabuki syndrome (also known as Niikawa-Kuroki syndrome) is a rare autosomal disorder, characterized by an unusual face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, mental retardation, and immunological defects. Point mutations and large intragenic deletions and duplications of the mixed lineage leukemia 2 (MLL2) and exons deletions of lysine demethylase 6A (-KDM6A) genes have been identified as its underlying causes. We report on the first description of a Moroccan Kabuki syndrome patient with typical facial features, developmental delay, finger pads, and other anomalies carrying a novel splice site mutation in the MLL2 gene that produces a truncated and likely pathogenetic form of MLL2 protein.

Non-association of Crohn's disease with NOD2 gene variants in Moroccan patients.

UNLABELLED: Crohn's disease is a chronic inflammatory bowel disease, with multifactorial traits, that can involve any part of the gastrointestinal tract. In recent years, a dozen genome-wide association scan and meta-analysis were published bringing the number of susceptibility alleles to more than 30 variations. However, the major susceptibility gene for Crohn's disease is NOD2, located on proximal 16q, which is involved in the innate immune response. Three main variants of this gene: two single nucleotide polymorphisms p.Arg702Trp and p.Gly908Arg substitutions and frameshift polymorphism p.Leu1007fsinsC are involved in susceptibility to Crohn's disease. There is no data about the frequency of these allelic variants in Moroccan patients with Crohn's disease. The aim of our study is to genotype the NOD2 gene to assess the involvement of these three variants in susceptibility to Crohn's disease for Moroccans. METHODS: We carried out genotyping for the three variants p.Arg702Trp, p.Gly908Arg and p.Leu1007fsinsC of NOD2 gene using PCR-sequencing among 101 Moroccan patients with Crohn's disease and 107 healthy controls. RESULTS: The three main variants of NOD2 gene were present in Moroccan patients with no significant difference compared to controls. CONCLUSION: This preliminary study shows no evidence association of NOD2 gene with Crohn's disease in the Moroccan population.

The first mutations in the MYH gene reported in Moroccan colon cancer patients.

BACKGROUND: Biallelic germline mutations in the MYH gene cause MYH-associated polyposis (MAP) disease, an autosomal recessive form of inherited colorectal cancer. People with MAP tend to develop attenuated multiple adenomatous colon polyps during their lifetime and will have an increased risk of colorectal cancer. Contrary to familial adenomatous polyposis, the number of adenomas is often lower in MAP (from 5 to 100), and even some patients have recently been reported with no identified adenomas. There have been many investigations into MAP that have been conducted in many different countries. Currently there is limited data on MAP in Morocco, and it is reasonable to think, that the prevalence of this form of genetic predisposition is as high as other autosomal recessive genetic diseases found in countries with high rates of consanguinity. The aim of this study is to examine the frequency of MYH mutations in colorectal cancer and/or attenuated polyposis in Moroccan patients. PATIENTS AND METHODS: The study population consisted of 62 patients; 52 with colorectal cancer, three of them had attenuated polyposis (2 to 99 adenomatous polyps). 10 other patients were referred to our department for polyposis without colorectal cancer. We carried out DNA analysis in 62 patients to screen for the three recurrent mutations c.494A>G (p.Tyr165Cys), c.1145G>A (p.Gly382Asp) and c.1185_1186dup, p.Glu396GlyfsX43, whereas 40 subjects were screened for germline MYH mutations in the whole coding sequence of the MYH gene by direct DNA sequencing. All these 40 patients, except two, had colorectal cancer without polyposis. RESULTS: Three patients with colorectal cancer and attenuated polyposis carried biallelic mutations in the MUTYH gene one with the c.494 A>G mutation, one with the c.1105delC mutation, one with the c.1145G>A mutation. One patient with 25 adenomas without colorectal cancer carried the c.1145G>A mutation at a homozygote state and one patient with 3 polyps was heterozygote for the mutation c.1145G>A. No biallelic mutations of MYH gene were detected in colorectal cancer patients and in patients with small number (<5) of polyps without colorectal cancer. CONCLUSION: We report the first biallelic MYH mutations in four Moroccan patients with clinical criteria of MAP; three of them had colorectal cancer with attenuated polyposis. No MYH mutations were found in colorectal patients without polyposis. Despite the relatively small sample size of the current study, our findings suggest that the MAP is not a frequent cause of colon cancer in Morocco as we had expected, and the molecular analysis of MYH gene should be restricted to patients displaying the classical phenotype of MAP.

[Spinal muscular atrophy: frequent cause of congenital hypotonia in Morocco]. / L'amyotrophie spinale infantile : cause fréquente des hypotonies congénitales au Maroc.

INTRODUCTION: Congenital hypotonia is a non specific symptom frequently seen in newborns and infants, and whose etiological diagnosis is often difficult due to the lack of specialized and affordable explorations. Childhood-onset proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by degeneration of the anterior horn cells of the spinal cord, leading to progressive paralysis with muscular atrophy. In more than 95% of the cases, it results from deletion of exon 7 of the SMN gene localized on 5q13, easily identified by molecular biology. OBJECTIVE: To determine the prevalence of the deletion of exon 7 of the SMN gene in congenital hypotonia with an unknown cause in Morocco. PATIENTS AND METHODS: We investigated the deletion of exon 7 of the SMN gene in 87 newborns and infants with congenital hypotonia. The cause of congenital hypotonia could not be determined in 60 of them, while 27 had electrophysiological evidence for an involvement of the anterior horn cells. RESULTS: The homozygous deletion of the SMN gene was detected in 23 of the newborns with unknown cause for hypotonia (38%) and in 21 of the infants whose electromyogram suggested infantile spinal amyotrophy (78%). CONCLUSION: This study underlines the advantages of a systematic search for the deletion of exon 7 of the SMN gene in every infant suffering from congenital hypotonia due to an unknown cause, particularly when the child's vital prognosis is at stake. This genetic test, easily implemented, should be systematically proposed after an attentive clinical evaluation in countries where the etiological diagnosis of congenital hypotonia is not systematic.

[Confirmation of the high prevalence in Morocco of the homozygous mutation c.144delC in the aurora kinase C gene (AURKC) in the teratozoospermia with large-headed spermatozoa]. / Confirmation de la forte prévalence au Maroc de la mutation homozygote c.144delC du gène aurora kinase C (AURKC) dans les tératozoospermies avec spermatozoïdes macrocéphales.

OBJECTIVES: To confirm the recurrent character of the mutation c.144delC in the aurora kinase C (AURKC) gene in Morocco and determine the indication and the interest of the research of this anomaly. PATIENTS AND METHODS: We looked for the mutation c.144delC in the AURKC gene in 18 infertile Moroccan patients. They were seen in medical genetic consultation within the framework of the preparatory assessment for medically-assisted procreation. Genomic DNA was extracted from 5 ml of EDTA-blood. The gene AURKC exon 3 was amplified by PCR then sequenced by using the Big-Dye Terminator V3.1 kit and an ABI Prism 310 Genetic Analyzer (Applied Biosystems). RESULTS: All the patients who had a typical phenotype with high rates of large-headed spermatozoa were homozygous for the mutation c.144delC in the AURKC gene. CONCLUSION: We confirm in this study the research interest of the recurrent mutation c.144delC in the gene AURKC in male infertility with high rates of large-headed spermatozoa. This molecular analysis avoids to many infertile couples unnecessary expenses and succession failures in case of use of medically-assisted procreation (MAP).

[Three cases of Hutchinson-Gilford progeria syndrome]. / Syndrome d'Hutchinson-Gilford (progéria). À propos de 3 cas.

Progeria, or Hutchinson-Gilford syndrome, is a rare genetic disease, characterized by several clinical features that develop in childhood, in particular, an accelerated aging aspect. Its incidence is 1-4 per 8 million newborns. Children with progeria syndrome usually appear normal at birth and in early infancy. Profound failure to thrive occurs during the 1st year. Characteristic facies, partial alopecia progressing to total alopecia, loss of subcutaneous fat, stiffness of joints, bone changes, and abnormal tightness of the skin over the abdomen and upper thighs usually become apparent during the 2nd to 3rd years. Motor and mental development is normal. Patients develop severe atherosclerosis. Death occurs as a result of complications of cardiac or cerebrovascular disease (heart attack or stroke) generally between ages 6 and 20 years. The diagnosis of Hutchinson-Gilford progeria syndrome (HGPS) is based on recognition of common clinical features and the detection of the recurrent p.Gly608Gly mutation in exon 11 of the LMNA gene, which is present in almost all individuals with HGPS. We present here 3 patients aged 5, 11, and 12 years referred to genetic consultation for dysmorphic facies and failure to thrive. After careful clinical examination and paraclinical assessment, the diagnosis of progeria syndrome was raised. We performed molecular analysis for the 3 patients by searching for the recurrent mutation c.1824C>T (p.Gly608Gly) of the LMNA gene, which was found only in 1 patient. We discuss the geneticist's role in the diagnosis of rare dysmorphic syndromes and their genetic counseling. We also analyze the clinical spectrum of HGPS by comparing the 3 patients.

Prevalence of MYH-associated polyposis related to three recurrent mutations in Morocco.

BACKGROUND: MYH-associated polyposis (MAP) is an autosomal recessive inherited disease. People with MAP tend to develop multiple adenomatous colon polyps during their lifetime and have an increased risk of colorectal cancer. MAP has only recently been described and there is much to be learned about the condition. Recessively inherited mutations in the base excision repair gene MYH have recently been associated with predisposition to colorectal adenomas and cancer. The epidemiology of MYH-associated polyposis (MAP) is poorly known in populations with high levels of consanguinity like North African populations, in particular in Morocco, and the MAP carrier frequency in the general Moroccan population has never been evaluated. The present study was carried out among the Moroccan population, using molecular epidemiology methods, to estimate the prevalence of homozygote or compound heterozygote genotype conferring MAP due to three mutations reported as recurrent in MAP: c.494A>G (Y165C), c.1145G>A (G382D) and c.1186_1187insGG (p.Glu396fsX42). METHODS: To estimate the prevalence of MYH mutations in Morocco, DNA extracted from blood samples of 400 healthy Moroccans was tested for recurrent MYH mutations using real-time PCR or DNA fragment analysis. Heterozygotes profiles were confirmed by direct sequencing. We searched for the mutations c.494A>G and c.1145G>A in 400 subjects, and the mutation c.1186_1187insGG in 250 subjects. RESULTS: One subject was heterozygous for c.494A>G (1/400 or 0.25%), three others for c.1145G>A (3/400 or 0.75%) and one was heterozygous for p.Glu396fsX42 (1/250 or 0.4%). The carrier frequency of one of these three mutations in the Moroccan population was calculated to be 1.4% and the frequency of homozygous or compound heterozygote for these three recurrent mutations is 1/10 000.These figures allowed one to estimate at 3500 the number of Moroccans with high risk of developing colon cancer due only to these three recurrent mutations. CONCLUSION: This preliminary study shows that the Moroccan population is at risk for MAP. This could help to define diagnosis strategies and patient care and may also have implications for genetic counselling.

Molecular analysis of Sanfilippo syndrome type C in Spain: seven novel HGSNAT mutations and characterization of the mutant alleles.

The Sanfilippo syndrome type C [mucopolysaccharidosis IIIC (MPS IIIC)] is caused by mutations in the HGSNAT gene, encoding an enzyme involved in heparan sulphate degradation. We report the first molecular study on several Spanish Sanfilippo syndrome type C patients. Seven Spanish patients, one Argentinean and three Moroccan patients were analysed. All mutant alleles were identified and comprised nine distinct mutant alleles, seven of which were novel, including four missense mutations (p.A54V, p.L113P, p.G424V and p.L445P) and three splicing mutations due to two point mutations (c.633+1G>A and c.1378-1G>A) and an intronic deletion (c.821-31_821-13del). Furthermore, we found a new single nucleotide polymorphism (SNP) (c.564-98T>C). The two most frequent changes were the previously described c.372-2A>G and c.234+1G>A mutations. All five splicing mutations were experimentally confirmed by studies at the RNA level, and a minigene experiment was carried out in one case for which no fibroblasts were available. Expression assays allowed us to show the pathogenic effect of the four novel missense mutations and to confirm that the already known c.710C>A (p.P237Q) is a non-pathogenic SNP. Haplotype analyses suggested that the two mutations (c.234+1G>A and c.372-2A>G) that were present in more than one patient have a common origin, including one (c.234+1G>A) that was found in Spanish and Moroccan patients.