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1.
Hemoglobin ; : 1-4, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38831725

RESUMEN

Congenital hemolytic anemia (CHA) is defined as the premature destruction of red blood cells (RBC) due to congenital or acquired defects. The hereditary form of hemolytic anemia can be divided into hemoglobinopathies, membranopathies, and enzymopathies. Hereditary spherocytosis (HS) is the most common inherited RBC membranopathy leading to congenital hemolytic anemia. To date; five genes have been associated with HS coding for cytoskeleton and transmembrane proteins, those genes are SPTB, SLC4A1, EPB42, ANK1, and SPTA1. Due to genetic heterogeneity, clinical exome sequencing (CES) was performed on four unrelated Moroccan patients referred for CHA investigation. Sanger sequencing and qPCR were performed to confirm CES results and to study the de novo character of identified variants. The molecular analysis revealed 3 novel mutations and one previously reported pathogenic variant of the SPTB gene confirming the diagnosis of HS in the four patients. Hereditary spherocytosis anemia is a genetically heterogenous disease which could be misdiagnosed clinically. The introduction of novel sequencing technologies can facilitate accurate genetic diagnosis, allowing an adapted care of the patient and his family.

2.
Am J Hum Genet ; 107(3): 527-538, 2020 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-32758447

RESUMEN

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.


Asunto(s)
Inflamación/genética , Interleucinas/genética , Peroxidasa/genética , Psoriasis/genética , Enfermedades de la Piel/genética , Adulto , Animales , Citocinas/genética , Trampas Extracelulares/genética , Femenino , Humanos , Inflamación/patología , Interleucina-1/genética , Interleucinas/metabolismo , Masculino , Ratones , Mutación/genética , Neutrófilos/metabolismo , Psoriasis/patología , Enfermedades Raras/enzimología , Enfermedades Raras/genética , Enfermedades Raras/patología , Piel/enzimología , Piel/patología , Enfermedades de la Piel/patología
3.
Breast Cancer Res Treat ; 194(1): 187-198, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35578052

RESUMEN

PURPOSE: Breast cancer (BC) is the most common form of female cancer around the world. BC is mostly sporadic, and rarely hereditary. These hereditary forms are mostly BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome. BRCA1 and BRCA2 genes are large and had some recurrent mutations specific to some populations. Through this work we analyze the most recurrent mutations in Moroccan population and compared them to a large review of other BRCA1/2 spectrum mutations in the MENA region. METHODS: We report in this work a series of 163 unrelated patients (the largest series of Moroccan patients) with familial breast and/or ovarian cancer, selected among patients referred to our oncogenetic outpatient clinic, from 2006 to 2021. To identify genetic variants in these two genes, different genetic analysis strategies have been carried out, using Sanger Sequencing DNA or Target Panel Sequencing. RESULTS: Pathogenic variants were identified in 27.6% of patients. The most frequent mutation identified in our patients was the c.1310_1313delAAGA, BRCA2 (33%), and three other mutations seem more frequent in the Moroccan population (33%) of all reported patients: c.798_799delTT, BRCA1; and c.3279delC, BRCA1; and c.7234_7235insG in BRCA2 gene. CONCLUSION: Through this work, we emphasize the importance of screening for BRCA1 and BRCA2 recurrent mutations in Moroccan patients. Other MENA (MENA: English-language acronym referring to the Middle East and North Africa region) countries had also some recurrent BRCA mutations, which will allow a fast and unexpensive first line genetic analysis and a precise molecular diagnosis. This will allow an adapted follow-up of the patients and a pre-symptomatic diagnosis of their relatives.


Asunto(s)
Neoplasias de la Mama , Genes BRCA1 , Genes BRCA2 , Neoplasias Ováricas , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Mutación , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/genética
4.
BMC Neurol ; 22(1): 292, 2022 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-35932018

RESUMEN

BACKGROUND: Congenital myasthenic syndromes (CMSs) are rare genetic diseases due to abnormalities of the neuromuscular junction leading to permanent or transient muscle fatigability and weakness. To date, 32 genes were found to be involved in CMSs with autosomal dominant and/or recessive inheritance patterns. CMS with acetylcholinesterase deficiency, in particular, was determined to be due to biallelic mutations of COLQ gene with early-onset clinical signs. Here, we report clinical features and novel molecular findings of COLQ-related CMS in a Moroccan patient with a review of the literature for this rare form. CASE PRESENTATION: In this study, we report the case of a 28-month-old Moroccan female patient with hypotonia, associated to axial muscle weakness, global motor delay, bilateral ptosis, unilateral partial visual field deficiency with normal ocular motility, and fatigable muscle weakness. Clinical exome sequencing revealed a novel homozygous deletion of exon 13 in COLQ gene, NM_005677.4(COLQ):c.(814+1_815-1)_(954+1_955-1) del p.(Gly272Aspfs*11). This finding was subsequently confirmed by quantitative real-time PCR (qPCR) in the proband and her parents. In silico analysis of protein-protein interaction network by STRING tool revealed that 12 proteins are highly associated to COLQ with an elevated confidence score. Treatment with Salbutamol resulted in clear benefits and recovery. CONCLUSIONS: This clinical observation illustrates the important place of next-generation sequencing in the precise molecular diagnosis of heterogeneous forms of CMS, the appropriate management and targeted treatment, and genetic counseling of families, with a better characterization of the mutational profile of this rare disease in the Moroccan population.


Asunto(s)
Síndromes Miasténicos Congénitos , Acetilcolinesterasa/genética , Acetilcolinesterasa/metabolismo , Preescolar , Colágeno/genética , Colágeno/metabolismo , Variaciones en el Número de Copia de ADN , Femenino , Homocigoto , Humanos , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Debilidad Muscular , Mutación/genética , Síndromes Miasténicos Congénitos/genética , Eliminación de Secuencia
5.
Nucleic Acids Res ; 47(6): 2822-2839, 2019 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-30698748

RESUMEN

The DNA methylation epigenetic signature is a key determinant during development. Rules governing its establishment and maintenance remain elusive especially at repetitive sequences, which account for the majority of methylated CGs. DNA methylation is altered in a number of diseases including those linked to mutations in factors that modify chromatin. Among them, SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain Containing 1) has been of major interest following identification of germline mutations in Facio-Scapulo-Humeral Dystrophy (FSHD) and in an unrelated developmental disorder, Bosma Arhinia Microphthalmia Syndrome (BAMS). By investigating why germline SMCHD1 mutations lead to these two different diseases, we uncovered a role for this factor in de novo methylation at the pluripotent stage. SMCHD1 is required for the dynamic methylation of the D4Z4 macrosatellite upon reprogramming but seems dispensable for methylation maintenance. We find that FSHD and BAMS patient's cells carrying SMCHD1 mutations are both permissive for DUX4 expression, a transcription factor whose regulation has been proposed as the main trigger for FSHD. These findings open new questions as to what is the true aetiology for FSHD, the epigenetic events associated with the disease thus calling the current model into question and opening new perspectives for understanding repetitive DNA sequences regulation.


Asunto(s)
Proteínas Cromosómicas no Histona/fisiología , Metilación de ADN , Proteínas de Homeodominio/genética , Repeticiones de Microsatélite/genética , Células Cultivadas , Reprogramación Celular/genética , Atresia de las Coanas/genética , Atresia de las Coanas/metabolismo , Metilación de ADN/genética , Epigénesis Genética/genética , Regulación de la Expresión Génica , Células HCT116 , Células HEK293 , Proteínas de Homeodominio/metabolismo , Humanos , Masculino , Microftalmía/genética , Microftalmía/metabolismo , Distrofia Muscular Facioescapulohumeral/genética , Distrofia Muscular Facioescapulohumeral/metabolismo , Distrofia Muscular Facioescapulohumeral/patología , Nariz/anomalías
6.
BMC Med Genet ; 21(1): 240, 2020 12 12.
Artículo en Inglés | MEDLINE | ID: mdl-33308164

RESUMEN

BACKGROUND: In Morocco, consanguinity rate is very high; which lead to an increase in the birth prevalence of infants with autosomal recessive disorders. Previously, it was difficult to diagnose rare autosomal recessive diseases. Next Generation Sequencing (NGS) techniques have considerably improved clinical diagnostics. A genetic diagnosis showing biallelic causative mutations is the requirement for targeted carrier testing in parents, prenatal and preimplantation genetic diagnosis in further pregnancies, and also for targeted premarital testing in future couples at risk of producing affected children by a known autosomal recessive disease. METHODS: In this report, we present our strategy to advise a future couple of first cousins, whose descendants would risk cystinosis; an autosomal recessive lysosomal disease caused by mutations in the CTNS gene. Indeed, our future husband's sister is clinically and biochemically diagnosed with cystinosis in early childhood. First, we opted to identify the patient's CTNS gene abnormality by using (NGS), then we searched for heterozygosity in the couple's DNA, which allows us to predict the exact risk of this familial disease in the future couple's offspring. RESULTS: We have shown that the future husband, brother of the patient is heterozygous for the familial mutation. On the other hand, his future wife did not inherit the familial mutation. Therefore, genetic counseling was reassuring for the risk of familial cystinosis in this couple's offspring. CONCLUSIONS: We report in this study, one of the major applications of (NGS), an effective tool to improve clinical diagnosis and to provide the possibility of targeted premarital carrier testing in couples at risk.


Asunto(s)
Sistemas de Transporte de Aminoácidos Neutros/genética , Consanguinidad , Cistinosis/genética , Asesoramiento Genético , Mutación , Adulto , Sistemas de Transporte de Aminoácidos Neutros/deficiencia , Cistinosis/diagnóstico , Cistinosis/patología , Femenino , Expresión Génica , Pruebas Genéticas , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Marruecos , Linaje , Riesgo
7.
J Am Soc Nephrol ; 29(7): 2000-2013, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29903748

RESUMEN

Background Steroid-sensitive nephrotic syndrome (SSNS) is a childhood disease with unclear pathophysiology and genetic architecture. We investigated the genomic basis of SSNS in children recruited in Europe and the biopsy-based North American NEPTUNE cohort.Methods We performed three ancestry-matched, genome-wide association studies (GWAS) in 273 children with NS (Children Cohort Nephrosis and Virus [NEPHROVIR] cohort: 132 European, 56 African, and 85 Maghrebian) followed by independent replication in 112 European children, transethnic meta-analysis, and conditional analysis. GWAS alleles were used to perform glomerular cis-expression quantitative trait loci studies in 39 children in the NEPTUNE cohort and epidemiologic studies in GWAS and NEPTUNE (97 children) cohorts.Results Transethnic meta-analysis identified one SSNS-associated single-nucleotide polymorphism (SNP) rs1063348 in the 3' untranslated region of HLA-DQB1 (P=9.3×10-23). Conditional analysis identified two additional independent risk alleles upstream of HLA-DRB1 (rs28366266, P=3.7×10-11) and in the 3' untranslated region of BTNL2 (rs9348883, P=9.4×10-7) within introns of HCG23 and LOC101929163 These three risk alleles were independent of the risk haplotype DRB1*07:01-DQA1*02:01-DQB1*02:02 identified in European patients. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS, with younger age of onset across all cohorts, and with increased odds of complete remission across histologies in NEPTUNE children. rs1063348 associated with decreased glomerular expression of HLA-DRB1, HLA-DRB5, and HLA-DQB1.Conclusions Transethnic GWAS empowered discovery of three independent risk SNPs for pediatric SSNS. Characterization of these SNPs provide an entry for understanding immune dysregulation in NS and introducing a genomically defined classification.


Asunto(s)
Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Síndrome Nefrótico/etnología , Síndrome Nefrótico/genética , Esteroides/uso terapéutico , África del Norte/etnología , Alelos , Población Negra/genética , Butirofilinas/genética , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Femenino , Francia/etnología , Estudio de Asociación del Genoma Completo , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB5/genética , Humanos , Italia/etnología , Masculino , Síndrome Nefrótico/tratamiento farmacológico , Fenotipo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , España/etnología , Población Blanca/genética
8.
Hum Mutat ; 39(3): 319-332, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29243349

RESUMEN

Autosomal recessive microcephaly or microcephaly primary hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The abnormal spindle-like microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster "abnormal spindle" gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological, and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities.


Asunto(s)
Microcefalia/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Preescolar , Cognición , Estudios de Cohortes , Familia , Femenino , Estudios de Asociación Genética , Geografía , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Microcefalia/epidemiología
9.
Am J Hum Genet ; 97(4): 535-45, 2015 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-26387595

RESUMEN

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.


Asunto(s)
Adenosina Trifosfatasas/genética , Amelogénesis Imperfecta/genética , Fibroblastos/patología , Pérdida Auditiva Sensorineural/genética , Proteínas de la Membrana/genética , Mutación/genética , Uñas Malformadas/genética , Peroxisomas/patología , ATPasas Asociadas con Actividades Celulares Diversas , Adolescente , Adulto , Estudios de Casos y Controles , Células Cultivadas , Niño , Preescolar , Femenino , Fibroblastos/metabolismo , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Linaje , Peroxisomas/metabolismo , Fenotipo , Pronóstico , Tasa de Supervivencia , Adulto Joven
10.
BMC Med Genet ; 19(1): 118, 2018 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-30021525

RESUMEN

BACKGROUND: Autosomal recessive primary microcephaly (MCPH) is a rare genetically heterogeneous disorder of neurogenic brain development characterized by a reduced head circumference at birth with no remarkable anomalies of brain architecture and variable degrees of intellectual impairment. Clinical and genetic heterogeneity in genetic disorders represent a major diagnostic challenge. CASE PRESENTATION: Two patients, 11 and 9 years old, born from consanguineous parents, were referred to the department of medical genetics at the National Institute of Health in Rabat. The diagnosis of MCPH was made, based on reduced head circumference without brain architecture abnormalities. The two patients were subject to the whole-exome sequencing, which allowed to diagnose a novel homozygous mutation c.1027C > T; p.Gln343* in exon 8 of WDR62, a gene already known to be related to MCPH. Sanger sequencing confirmed the segregation of the mutation in the family. CONCLUSION: Our data expends the spectrum of mutations in WDR62 gene, proves the efficiency and cost-effectiveness of whole exome sequencing for the molecular diagnosis of genetically heterogeneous disorders such MCPH. Exome sequencing led to the rapid and cost-effective identification of a novel homozygous mutation in WDR62 gene, thereby facilitating genetic counseling.


Asunto(s)
Microcefalia/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Encéfalo/anomalías , Proteínas de Ciclo Celular , Niño , Femenino , Homocigoto , Humanos , Masculino , Linaje
11.
BMC Pediatr ; 18(1): 90, 2018 02 27.
Artículo en Inglés | MEDLINE | ID: mdl-29486744

RESUMEN

BACKGROUND: Epilepsy regroups a common and diverse set of chronic neurological disorders that are characterized by spontaneous, unprovoked, and recurrent epileptic seizures. Epilepsies have a highly heterogeneous background with a strong genetic contribution and various mode of inheritance. X-linked epilepsy usually manifests as part of a syndrome or epileptic encephalopathy. The variability of clinical manifestations of X-linked epilepsy may be attributed to several factors including the causal genetic mutation, making diagnosis, genetic counseling and treatment decisions difficult. We report the description of a Moroccan family referred to our genetic department with X-linked epileptic seizures as the only initial diagnosis. CASE PRESENTATION: Knowing the new contribution of Next-Generation Sequencing (NGS) for clinical investigation, and given the heterogeneity of this group of disorders we performed a Whole-Exome Sequencing (WES) analysis and co-segregation study in several members of this large family. We detected a novel pathogenic PLP1 missense mutation c.251C > A (p.Ala84Asp) allowing us to make a diagnosis of Pelizaeus-Merzbacher Disease for this family. CONCLUSION: This report extends the spectrum of PLP1 mutations and highlights the diagnostic utility of NGS to investigate this group of heterogeneous disorders.


Asunto(s)
Secuenciación del Exoma , Mutación Missense , Proteína Proteolipídica de la Mielina/genética , Enfermedad de Pelizaeus-Merzbacher/diagnóstico , Enfermedad de Pelizaeus-Merzbacher/genética , Preescolar , Familia , Femenino , Marcadores Genéticos , Humanos , Masculino , Marruecos , Linaje
12.
BMC Pediatr ; 18(1): 138, 2018 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-29665810

RESUMEN

After publication of the original article [1] it was brought to our attention that author Bouchra Ouled Amar Bencheikh was incorrectly included as Bouchra Oulad Amar Bencheikh.

13.
Cytogenet Genome Res ; 153(2): 66-72, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29248929

RESUMEN

Unbalanced translocations involving X and Y chromosomes are rare and associated with a contiguous gene syndrome. The clinical phenotype is heterogeneous including mainly short stature, chondrodysplasia punctata, ichthyosis, hypogonadism, and intellectual disability. Here, we report 2 brothers with peculiar gestalt, short stature, and hearing loss, who harbor an X/Y translocation. Physical examination, brainstem acoustic potential evaluation, bone age, hormonal assessment, and X-ray investigations were performed. Because of their dysmorphic features, karyotyping, FISH, and aCGH were carried out. The probands had short stature, hypertelorism, midface hypoplasia, sensorineural hearing loss, normal intelligence as well as slight radial and ulnar bowing with brachytelephalangy. R-banding identified a derivative X chromosome with an abnormally expanded short arm. The mother was detected as a carrier of the same aberrant X chromosome. aCGH disclosed a 3.1-Mb distal deletion of chromosome region Xp22.33pter. This interval encompasses several genes, especially the short stature homeobox (SHOX) and arylsulfatase (ARSE) genes. The final karyotype of the probands was: 46,Y,der(X),t(X;Y)(p22;q12).ish der(X)(DXYS129-,DXYS153-)mat.arr[hg19] Xp22.33(61091_2689408)×1mat,Xp22.33(2701273_3258404)×0mat,Yq11.222q12 (21412851_59310245)×2. Herein, we describe a Moroccan family with a maternally inherited X/Y translocation and discuss the genotype-phenotype correlations according to the deleted genes.


Asunto(s)
Anomalías Múltiples/genética , Arilsulfatasas/genética , Cromosomas Humanos X/genética , Cromosomas Humanos Y/genética , Pérdida Auditiva Bilateral/genética , Pérdida Auditiva Sensorineural/genética , Translocación Genética , Arilsulfatasas/deficiencia , Cromosomas Humanos X/ultraestructura , Cromosomas Humanos Y/ultraestructura , Consanguinidad , Femenino , Humanos , Hipertelorismo/genética , Recién Nacido , Cariotipificación , Masculino , Persona de Mediana Edad , Marruecos , Linaje , Fenotipo , Radio (Anatomía)/anomalías , Escoliosis/genética , Hermanos , Cúbito/anomalías , Adulto Joven
14.
Am J Med Genet A ; 170(9): 2462-5, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27380734

RESUMEN

Anauxetic dysplasia (AAD, OMIM 607095) is a rare skeletal dysplasia inherited as an autosomal recessive trait, which is caused by mutations in RMRP and allelic to a more common disorder, cartilage hair hypoplasia (CHH). CHH is a multi-system disorder with a variety of extraskeletal changes. Whereas AAD is a bone-restricted disorder with a more severe skeletal phenotype: affected individuals are extremely short and complicated by orthopedic morbidity, and the radiological changes include modification of the vertebral bodies and epiphyseal dysplasia of the hip, as well as generalized metaphyseal dysplasia and severe brachydactyly. Recently, genetic heterogeneity for AAD was proposed, because a familial case (two affected sibs) with an AAD-identical phenotype had compound heterozygous mutations in POP1, encoding a molecule functionally related to the gene product of RMRP. We report here a 5-year-old boy with the same phenotype born to a consanguineous couple. We identified a novel homozygous POP1 mutation (c.1744C>T, p.P582S) in the boy and the heterozygosity in the parents. It may be rational to coin the POP1-associated skeletal phenotype AAD type 2. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Enanismo/diagnóstico , Enanismo/genética , Estudios de Asociación Genética , Mutación , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Fenotipo , Ribonucleoproteínas/genética , Alelos , Preescolar , Biología Computacional/métodos , Consanguinidad , Análisis Mutacional de ADN , Exones , Homocigoto , Humanos , Masculino , Radiografía
15.
Am J Med Genet A ; 170A(2): 460-465, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26463668

RESUMEN

Spondylo-meta-epiphyseal dysplasia (SMED), short limb-abnormal calcification type (SMED, SL-AC), is a very rare autosomal recessive disorder with various skeletal changes characterized by premature calcification leading to severe disproportionate short stature. Twenty-two patients have been reported until now, but only five mutations (four missense and one splice-site) in the conserved sequence encoding the tyrosine kinase domain of the DDR2 gene has been identified. We report here a novel DDR2 missense mutation, c.370C > T (p.Arg124Trp) in a Moroccan girl with SMED, SL-AC, identified by whole exome sequencing. Our study has expanded the mutational spectrum of this rare disease and it has shown that exome sequencing is a powerful and cost-effective tool for the diagnosis of clinically heterogeneous disorders such as SMED.


Asunto(s)
Calcinosis/genética , Calcinosis/patología , Enanismo/genética , Enanismo/patología , Exoma/genética , Mutación Missense/genética , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Proteínas Tirosina Quinasas Receptoras/genética , Receptores Mitogénicos/genética , Preescolar , Receptores con Dominio Discoidina , Femenino , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Marruecos
16.
Nucleic Acids Res ; 42(Database issue): D1020-6, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24234438

RESUMEN

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.


Asunto(s)
Bases de Datos de Ácidos Nucleicos , Frecuencia de los Genes , Enfermedades Genéticas Congénitas/genética , Mutación , Marcadores Genéticos , Genoma Humano , Humanos , Internet , Farmacogenética
17.
Nat Genet ; 39(4): 454-6, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17353897

RESUMEN

Neural progenitor proliferation and migration influence brain size during neurogenesis. We report an autosomal recessive microcephaly syndrome cosegregating with a homozygous balanced translocation between chromosomes 3p and 10q, and we show that a position effect at the breakpoint on chromosome 3 silences the eomesodermin transcript (EOMES), also known as T-box-brain2 (TBR2). Together with the expression pattern of EOMES in the developing human brain, our data suggest that EOMES is involved in neuronal division and/or migration. Thus, mutations in genes encoding not only mitotic and apoptotic proteins but also transcription factors may be responsible for malformative microcephaly syndromes.


Asunto(s)
Agenesia del Cuerpo Calloso , Silenciador del Gen , Homocigoto , Microcefalia/genética , Proteínas de Dominio T Box/genética , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Cromosomas Humanos Par 10 , Cromosomas Humanos Par 3 , Análisis Mutacional de ADN , Humanos , Masculino , Linaje , Translocación Genética
18.
BMC Oral Health ; 15: 14, 2015 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-25636655

RESUMEN

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


Asunto(s)
Amelogénesis Imperfecta/genética , Proteínas del Esmalte Dental/genética , Fibromatosis Gingival/genética , Eliminación de Secuencia/genética , Alanina/genética , Secuencia de Bases , Niño , Codón sin Sentido/genética , Citosina , Exones/genética , Femenino , Mutación del Sistema de Lectura/genética , Hiperplasia Gingival/genética , Homocigoto , Humanos , Leucina/genética , Marruecos , Síndrome , Timina
19.
Hum Mutat ; 35(10): 1203-10, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25044680

RESUMEN

Rare, atypical, and undiagnosed autosomal-recessive disorders frequently occur in the offspring of consanguineous couples. Current routine diagnostic genetic tests fail to establish a diagnosis in many cases. We employed exome sequencing to identify the underlying molecular defects in patients with unresolved but putatively autosomal-recessive disorders in consanguineous families and postulated that the pathogenic variants would reside within homozygous regions. Fifty consanguineous families participated in the study, with a wide spectrum of clinical phenotypes suggestive of autosomal-recessive inheritance, but with no definitive molecular diagnosis. DNA samples from the patient(s), unaffected sibling(s), and the parents were genotyped with a 720K SNP array. Exome sequencing and array CGH (comparative genomic hybridization) were then performed on one affected individual per family. High-confidence pathogenic variants were found in homozygosity in known disease-causing genes in 18 families (36%) (one by array CGH and 17 by exome sequencing), accounting for the clinical phenotype in whole or in part. In the remainder of the families, no causative variant in a known pathogenic gene was identified. Our study shows that exome sequencing, in addition to being a powerful diagnostic tool, promises to rapidly expand our knowledge of rare genetic Mendelian disorders and can be used to establish more detailed causative links between mutant genotypes and clinical phenotypes.


Asunto(s)
Consanguinidad , Exoma , Genes Recesivos/genética , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Adolescente , Adulto , Árabes , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Linaje , Análisis de Secuencia de ADN , Adulto Joven
20.
BMC Genet ; 15: 156, 2014 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-25544508

RESUMEN

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.


Asunto(s)
Arilamina N-Acetiltransferasa/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Citocromo P-450 CYP2E1/genética , Antituberculosos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Recién Nacido , Isoniazida/efectos adversos , Marruecos/epidemiología , Polimorfismo de Nucleótido Simple , Prevalencia , Factores de Riesgo
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