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1.
Genet Med ; 24(10): 2194-2203, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36001086

RESUMEN

PURPOSE: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. METHODS: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. RESULTS: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. CONCLUSION: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration.


Asunto(s)
Complejo Mediador , Microcefalia , Enfermedades Neurodegenerativas , Animales , Humanos , Homocigoto , Complejo Mediador/genética , Microcefalia/genética , Enfermedades Neurodegenerativas/genética , ARN , Pez Cebra/genética
2.
Clin Genet ; 102(2): 157-160, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35796208

RESUMEN

Our study included 13 patients diagnosed with neuronal ceroidlipofuscinosis. It is a group of rare genetically-determined neurodegenerativediseases characterized by clinical and genetic heterogeneity. brain MRI andelectroencephalogram facilitate diagnosis.


Asunto(s)
Lipofuscinosis Ceroideas Neuronales , Electroencefalografía , Humanos , Imagen por Resonancia Magnética , Lipofuscinosis Ceroideas Neuronales/diagnóstico por imagen , Lipofuscinosis Ceroideas Neuronales/genética
3.
Hum Genet ; 140(1): 43-57, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33108537

RESUMEN

Globozoospermia is a rare phenotype of primary male infertility inducing the production of round-headed spermatozoa without acrosome. Anomalies of DPY19L2 account for 50-70% of all cases and the entire deletion of the gene is by far the most frequent defect identified. Here, we present a large cohort of 69 patients with 20-100% of globozoospermia. Genetic analyses including multiplex ligation-dependent probe amplification, Sanger sequencing and whole-exome sequencing identified 25 subjects with a homozygous DPY19L2 deletion (36%) and 14 carrying other DPY19L2 defects (20%). Overall, 11 deleterious single-nucleotide variants were identified including eight novel and three already published mutations. Patients with a higher rate of round-headed spermatozoa were more often diagnosed and had a higher proportion of loss of function anomalies, highlighting a good genotype phenotype correlation. No gene defects were identified in patients carrying < 50% of globozoospermia while diagnosis efficiency rose to 77% for patients with > 50% of globozoospermia. In addition, results from whole-exome sequencing were scrutinized for 23 patients with a DPY19L2 negative diagnosis, searching for deleterious variants in the nine other genes described to be associated with globozoospermia in human (C2CD6, C7orf61, CCDC62, CCIN, DNAH17, GGN, PICK1, SPATA16, and ZPBP1). Only one homozygous novel truncating variant was identified in the GGN gene in one patient, confirming the association of GGN with globozoospermia. In view of these results, we propose a novel diagnostic strategy focusing on patients with at least 50% of globozoospermia and based on a classical qualitative PCR to detect DPY19L2 homozygous deletions. In the absence of the latter, we recommend to perform whole-exome sequencing to search for defects in DPY19L2 as well as in the other previously described candidate genes.


Asunto(s)
Infertilidad Masculina/genética , Proteínas de la Membrana/genética , Teratozoospermia/genética , Hormonas Testiculares/genética , Estudios de Cohortes , Eliminación de Gen , Estudios de Asociación Genética/métodos , Pruebas Genéticas/métodos , Homocigoto , Humanos , Masculino , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Espermatozoides/anomalías , Secuenciación del Exoma/métodos
4.
Neuropediatrics ; 49(5): 339-341, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30011403

RESUMEN

ATP1A3 mutations have now been recognized in infants, children, and adults presenting with a diverse group of neurological phenotypes, including rapid-onset dystonia-parkinsonism, alternating hemiplegia of childhood, and most recently, cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss syndrome. The phenotypic spectrum of ATP1A3-related neurological disorders continues to expand. In this case study, we report on early life epilepsy with episodic apnea potentially secondary to ATP1A3 mutation in a Tunisian child.


Asunto(s)
Apnea/genética , Epilepsia/genética , ATPasa Intercambiadora de Sodio-Potasio/genética , Humanos , Lactante , Masculino
5.
Tunis Med ; 93(3): 170-4, 2015 Mar.
Artículo en Francés | MEDLINE | ID: mdl-26367406

RESUMEN

BACKGROUND: Marshall syndrome is a rare autosomal dominant skeletal dysplasia. It associates a particular facial dysmorphism with midface hypoplasia, ocular abnormalities and sensorineural hearing loss. It is caused by heterozygous mutations in COL11A1 gene coding the 1 chain of collagen XI. Stickler syndrome is the principal differential diagnosis of Marshall syndrome. AIM: Clinical and radiological study of Marshall syndrome in a Tunisian family with a linkage study of the COL11A1 gene to this disease. METHODS: We report the clinical and the radiological findings of a Tunisian family including 8 members affected by Marshall syndrome. The linkage of the COL11A1 gene to this disease was tested using the polymorphic microsatellite markers of DNA. RESULTS: A variability of the clinical expression of Marshall syndrome was reported. Specific Marshall phenotype and an overlapping phenotype between the Marshall and Stickler syndromes were observed among the affected members of this family. The ocular manifestations were also heterogeneous. Marshall syndrome's specific radiological signs were found. The linkage study supports the linkage of the abnormal phenotype to the COL11A1 gene. CONCLUSION: There is a variability of the clinical expression among the affected members of the study's family. We will continue searching the causative mutation to establish a clear genotype- phenotype correlation.


Asunto(s)
Catarata/genética , Colágeno Tipo XI/deficiencia , Anomalías Craneofaciales/genética , Pérdida Auditiva Sensorineural/genética , Mutación , Osteocondrodisplasias/genética , Adulto , Anciano , Preescolar , Colágeno Tipo XI/genética , Femenino , Humanos , Recién Nacido , Masculino , Linaje , Túnez , Adulto Joven
6.
BMC Ophthalmol ; 11: 35, 2011 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-22103961

RESUMEN

BACKGROUND: To identify the genetic defect associated with autosomal recessive congenital cataract (ARCC), mental retardation (MR) and ARCC, MR and microcephaly present in most patients in four Tunisian consanguineous families. METHODS: We screened four genes implicated in congenital cataract by direct sequencing in two groups of patients; those affected by ARCC associated to MR and those who presented also microcephaly. Among its three genes PAX6, PITX3 and HSF4 are expressed in human brain and one gene LIM2 encodes for the protein MP20 that interact with the protein galectin-3 expressed in human brain and plays a crucial role in its development. All genes were screened by direct sequencing in two groups of patients; those affected by ARCC associated to MR and those who presented also microcephaly. RESULTS: We report no mutation in the four genes of congenital cataract and its flanking regions. Only variations that did not segregate with the studied phenotypes (ARCC associated to MR, ARCC associated with MR and microcephaly) are reported. We detected three intronic variations in PAX6 gene: IVS4 -274insG (intron 4), IVS12 -174G>A (intron12) in the four studied families and IVS4 -195G>A (intron 4) in two families. Two substitutions polymorphisms in PITX3 gene: c.439 C>T (exon 3) and c.930 C>A (exon4) in one family. One intronic variation in HSF4 gene: IVS7 +93C>T (intron 7) identified in one family. And three intronic substitutions in LIM2 gene identified in all four studied families: IVS2 -24A>G (intron 2), IVS4 +32C>T (intron 4) and c.*15A>C (3'-downstream sequence). CONCLUSION: Although the role of the four studied genes: PAX6, PITX3, HSF4 and LIM2 in both ocular and central nervous system development, we report the absence of mutations in all studied genes in four families with phenotypes associating cataract, MR and microcephaly.


Asunto(s)
Catarata/congénito , Catarata/genética , Proteínas de Unión al ADN/genética , Proteínas del Ojo/genética , Proteínas de Homeodominio/genética , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Mutación/genética , Factores de Transcripción/genética , Adolescente , Adulto , Catarata/complicaciones , Niño , Consanguinidad , Análisis Mutacional de ADN , Familia , Femenino , Frecuencia de los Genes , Factores de Transcripción del Choque Térmico , Humanos , Intrones/genética , Masculino , Microcefalia/genética , Túnez , Adulto Joven
7.
Mol Vis ; 16: 582-5, 2010 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-20376326

RESUMEN

PURPOSE: The PITX3 (pituitary homeobox 3) gene encodes for a homeobox bicoid-like transcription factor. When one allele is mutated, it leads to dominant cataract and anterior segment mesenchymal dysgenesis in humans. When both copies are mutated, homozygous mutation contributes to microphtalmia with brain malformations. In the current study, a family with autosomal recessive congenital cataract (ARCC) associated with mental retardation (MR) was examined to identify PITX3 mutations. METHODS: Sequencing of the PITX3 gene was performed on two affected and three unaffected members of the studied Tunisian family. The results were analyzed with Sequencing Analysis 5.2 and SeqScape. RESULTS: No mutation in the four exons of PITX3 was revealed. Two substitution polymorphisms, c.439C>T and c.930C>A, were detected in exons 3 and 4, respectively. These alterations did not segregate with the disease. CONCLUSIONS: Although PITX3 was shown to be essential to normal embryonic eye and brain development in vertebrates, we report the absence of PITX3 mutations in a family presenting congenital cataract and mental retardation.


Asunto(s)
Catarata/congénito , Catarata/genética , Proteínas de Homeodominio/genética , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Mutación/genética , Factores de Transcripción/genética , Adolescente , Adulto , Catarata/complicaciones , Niño , Preescolar , Familia , Femenino , Humanos , Masculino , Linaje , Túnez , Adulto Joven
8.
Am J Med Genet A ; 146A(14): 1825-7, 2008 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-18553510

RESUMEN

We report on a 22-day-old Tunisian boy born to consanguineous (first-cousin) parents (F = 1/16). The patient presents wide forehead with frontal encephalocele, wide anterior fontanel, marked hypertelorism, coloboma of the upper lids, proptosis, congenital glaucoma, broad nose, syndactyly between fingers 3 and 4, hypoplastic 3rd, 4th and 5th toes with nail dysplasia, hypospadias with cleft glans, bifid scrotum. Brain MRI showed right frontal encephalocele with anomalies of the cortical gyration without any corpus callosum abnormality. Normal chromosomes and parents' consanguinity are suggestive of autosomal recessive inheritance. Facial midline anomalies associated with limb and genitourinary anomalies is very uncommon. We present the third case reported in the literature.


Asunto(s)
Anomalías Múltiples/genética , Disostosis Craneofacial/genética , Anomalías Urogenitales/genética , Anomalías Múltiples/patología , Consanguinidad , Disostosis Craneofacial/clasificación , Disostosis Craneofacial/patología , Genes Recesivos , Humanos , Recién Nacido , Masculino , Fenotipo , Síndrome , Anomalías Urogenitales/patología
9.
Sante ; 18(4): 199-203, 2008.
Artículo en Francés | MEDLINE | ID: mdl-19810614

RESUMEN

UNLABELLED: Down syndrome (Trisomy 21) is the most common fetal chromosomal abnormality in humans. Its clinical signs are now well known. Methods for prenatal screening have advanced substantially in the past two decades. OBJECTIVE: To describe our experience with prenatal diagnosis of Down syndrome, including the indications, methods and results. MATERIAL AND METHODS: This retrospective study examined cases over a 4-year period. We adopted a sequential screening strategy for patients followed in our department since the beginning of their pregnancies after informed consent. We proposed first trimester ultrasound that measured nuchal translucency thickness and followed it with maternal serum screening. Some patients underwent screening during the second trimester or third trimester ultrasound. To assess the results, we studied the mothers' epidemiological characteristics and analysed the circumstances of prenatal diagnosis of trisomy 21 (T21). RESULTS/DISCUSSION: We identified 22 cases of T21 during the study period, for a total prevalence of 0.98 per thousand. The diagnosis was prenatal in 13 cases, mainly due to ultrasound signs. Of the 14 patients seen prenatally, only 8 were followed from early pregnancy. Five had enlarged nuchal translucency (> 95th percentile). Three had positive second trimester serum screening tests. One patient had amniocentesis planned because of her age (table 1). T21 was diagnosed in the second trimester in two cases and in the third trimester in three. The major morphological abnormalities observed were cardiac. We found an atrioventricular canal defect in four cases, and fetal hydrops in two cases (Table 2). The median gestational age at diagnosis of T21 in this study was 21 weeks. The diagnosis was missed in one patient followed throughout pregnancy in our unit. The median gestational age at termination of pregnancy was 22 weeks. Only one patient chose not to terminate the pregnancy. Her fetus, delivered at term, had no major pathologies. CONCLUSION: The establishment of a screening strategy for trisomy 21 in Tunisia is necessary to reduce handicaps. It should begin by expanding first-trimester ultrasound with nuchal translucency measurement. At the same time, serum marker testing should be offered to all patients. Routine amniocentesis for advanced maternal age should be avoided.


Asunto(s)
Síndrome de Down/diagnóstico por imagen , Ultrasonografía Prenatal , Adulto , Femenino , Humanos , Persona de Mediana Edad , Embarazo , Estudios Retrospectivos , Túnez
10.
Tunis Med ; 86(11): 973-7, 2008 Nov.
Artículo en Francés | MEDLINE | ID: mdl-19213487

RESUMEN

BACKGROUND: The fragile X syndrome was the most frequent etiology of hereditary mental retardation but the clinical diagnosis is not easy and the individual clinical symptoms were not specific so the confirmation will be made par molecular study of the gene of the fragile X syndrome. The aim of our study is to realise the molecular diagnosis of the fragile X syndrome in 200 Tunisian boys with mental retardation. Our results shows that the frequency of the fragile X syndrome is 7,6%. In the most cases there is a family history of mental retardation with medium age at 11 years. All the boys with the full mutation have mental retardation, dysmorphic features and macro-orchidism (pubescent boy) CONCLUSION: The screening of the molecular abnormalities of FMRI gene must be realised in every boy with mental retardation or boy with delayed speech without any identified etiology. The earlier diagnosis is important for genetic counselling.


Asunto(s)
Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/genética , Anomalías Múltiples/genética , Adolescente , Adulto , Niño , Preescolar , Anomalías Craneofaciales/genética , Asesoramiento Genético , Marcadores Genéticos , Pruebas Genéticas , Humanos , Discapacidad Intelectual/genética , Masculino , Mutación , Linaje , Pubertad , Estudios Retrospectivos , Testículo/anomalías , Túnez
11.
Semin Arthritis Rheum ; 36(6): 397-401, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17276496

RESUMEN

OBJECTIVES: To identify the frequency and distribution of familial Mediterranean fever (FMF) gene (MEFV) mutations in Tunisian patients. PATIENTS AND METHODS: This study was performed in the Genetic Department of Tunis University Hospital. A clinical diagnosis of FMF was made according to published criteria. Mutation screening of the MEFV gene was performed in the Human Genetic Laboratory of the "Faculté de Medecine de Tunis" for 8 mutations including the 5 most common known mutations M694V, V726A, M694l, M680l, and E148Q. The tests performed were polymerase chain reaction (PCR) restriction-digestion for M694V, V726A, M680l, R761H, E148Q; amplification refractory mutation system for A744S, M694l; and PCR-electrophoresis assay for l692del. RESULTS: Of the 139 unrelated patients investigated, 61 (44%) had 1 or 2 mutations. In 78 (56%) probands no mutation was identified: 28 patients were homozygous; 16 were compound-heterozygous; 2 had complex alleles; and 17 had only 1 identifiable mutation. Of the mutations, M680l, M694V, M694l, V726A, A744S, R761H, l692DEL, and E148Q accounted for 32, 27, 13, 5, 3, 1, 1, and 18%, respectively. CONCLUSION: The profile of the MEFV gene mutations in the Tunisian population is concordant with other Arab populations but with some differences. M680l is the most common mutation, while V726A, the commonest mutation among Arabs, is rare in our population.


Asunto(s)
Proteínas del Citoesqueleto/genética , Fiebre Mediterránea Familiar/genética , Predisposición Genética a la Enfermedad , Mutación , Adolescente , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Fiebre Mediterránea Familiar/etnología , Fiebre Mediterránea Familiar/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pirina , Túnez/epidemiología
12.
Tunis Med ; 85(10): 885-90, 2007 Oct.
Artículo en Francés | MEDLINE | ID: mdl-18236814

RESUMEN

Treacher Collins syndrome was first mentioned by Thompson in 1847, and described by Treacher Collins in 1900, then it was called mandibulo-facial dysostosis and well defined by Franceschetti in 1949. It is a very rare affection occurring lin 50.000 live births, which includes facial and auricular anomalies leading to functional, morphological and psychological difficulties due to related handicaps. Treacher Collins syndrome is inherited as autosomal dominant pattern with a variable expressivity and incomplete penetrance of "TCOF1" gene localized at 5q31.3q32. Today the gene is well identified and several mutations have been reported. In this paper we report the case of 4 Tunisian unrelated girls with Treacher Collins syndrome. One of them was born from an affected father. Clinical diagnostic was performed between age 12 days and 2 years demonstrating the large dysmorphic expression. Main clinical features were present in all reported cases. Family at risk might have genetic counselling and probably prenatal diagnostic in some situations. Out of our observations, we gave genetic counselling and proposed ultrasound prenatal diagnosis for two families without molecular study.


Asunto(s)
Disostosis Mandibulofacial/patología , Preescolar , Sordera/patología , Oído Medio/anomalías , Huesos Faciales/anomalías , Femenino , Humanos , Lactante , Recién Nacido , Cariotipificación , Disostosis Mandibulofacial/genética
13.
Eur J Dermatol ; 27(5): 519-523, 2017 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-28739549

RESUMEN

Sitosterol is the most abundant plant sterol found in our diet. Sitosterolemia (OMIM 210250), also known as phytosterolaemia, is a rare autosomal recessive disease caused by the inability to efficiently excrete plant sterol, and is characterized by cutaneous xanthomas and accelerated atherosclerosis. Sitosterolaemia is caused by homozygous or compound heterozygous mutations in either ABCG5 or ABCG8 (both on chromosome 2p21), which encode the sterol efflux transporter ABCG5 (sterolin-1) and ABCG8 (sterolin-2), respectively. To investigate a Tunisian family with several members who manifested with generalized cutaneous xanthomas, whereas others had only isolated xanthelasmas. Genetic analysis was performed based on exome sequencing of DNA obtained from five affected individuals and one unaffected individual from a Tunisian family. RESULTS: A novel mutation in the ABCG8 gene, designated c.965-1G>C, was identified by exome sequencing in the members of this family. The homozygous form was associated with generalized cutaneous xanthomatosis while the heterozygous form was linked to isolated xanthelasmas. Our results indicate a gene dosage effect of ABCG8 and suggest that individuals at risk should be followed closely.


Asunto(s)
Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/genética , Hipercolesterolemia/genética , Enfermedades Intestinales/genética , Errores Innatos del Metabolismo Lipídico/genética , Mutación , Fitosteroles/efectos adversos , Enfermedades de la Piel/genética , Xantomatosis/genética , Adulto , Femenino , Heterocigoto , Homocigoto , Humanos , Masculino , Linaje , Fitosteroles/genética , Túnez
14.
Invest Ophthalmol Vis Sci ; 47(8): 3487-95, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16877420

RESUMEN

PURPOSE: To study Bardet-Biedl syndrome (BBS) in the Tunisian population and determine the presence of triallelism in the eight identified BBS genes. METHODS: DNA samples were collected from 19 consanguineous Tunisian families with BBS. Genome-wide scans were performed with microsatellite markers in 12 families, and two-point linkage analyses were performed. Direct sequencing was used to screen patients with BBS for mutations in all eight identified BBS genes. RESULTS: Mutations in the BBS genes were identified in nine families. In addition, a large consanguineous family (57004) showed linkage to the BBS7 locus, although no mutation was identified. Five novel mutations were present in the nine families: one in BBS2 (c.565C>T, p.ArgR189Stop), one in BBS5 (c.123delA, p.Gly42GlufsX11), one in BBS7 (g.47247455_47267458del20004insATA, p.Met284LysfsX7), and two in BBS8 (c.459+1G>A, p.Pro101LeufsX12 and c.355_356insGGTGGAAGGCCAGGCA, p.Thr124ArgfsX43). CONCLUSIONS: All families in which mutations were identified show changes in both copies of the mutant gene, and inheritance patterns in all families are consistent with autosomal recessive inheritance excluding any evidence of triallelism in the BBS genes in Tunisia.


Asunto(s)
Alelos , Síndrome de Bardet-Biedl/genética , Consanguinidad , Femenino , Genes Recesivos , Prueba de Complementación Genética , Ligamiento Genético , Pruebas Genéticas , Genotipo , Humanos , Masculino , Repeticiones de Microsatélite , Mutación , Linaje , Proteínas/genética , Túnez
15.
Clin Dysmorphol ; 14(1): 23-25, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15602089

RESUMEN

Cleft palate with ankyloglossia (CPX; OMIM 303400) is inherited as a Mendelian semidominant X-Linked disorder. Linkage studies resulted in mapping CPX to Xq13-q 21-31 region. TBX22 was identified as causing CPX. We report a new mutation in a Tunisian family and the first Arab family with X-Linked cleft palate and ankyloglossia. The family includes 6 affected members, 4 males and 2 females. Linkage study was performed using 9 microsatellite markers surrounding the CPX locus with a maximum lod score 1.81 at theta=0 with several markers. Sequence analysis of TBX22 gene revealed a novel change c.358C>T in exon 3 (R120W) located in the T-BOX domain; this change was present in all affected members and none of the 100 controls. A second modification in exon 4 (c.559G>A) predicted to result in a nonconservative substitution (E187 K) was present in the affected members but also in 2 controls, suggesting a polymorphism which functional role cannot be excluded without further study.


Asunto(s)
Fisura del Paladar/genética , Familia , Mutación , Proteínas de Dominio T Box/genética , Femenino , Humanos , Masculino , Linaje , Túnez
16.
Eur J Hum Genet ; 23(8): 1025-32, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25351776

RESUMEN

Duplications in the ~2 Mb desert region upstream of SOX9 at 17q24.3 may result in familial 46,XX disorders of sex development (DSD) without any effects on the XY background. A balanced translocation with its breakpoint falling within the same region has also been described in one XX DSD subject. We analyzed, by conventional and molecular cytogenetics, 19 novel SRY-negative unrelated 46,XX subjects both familial and sporadic, with isolated DSD. One of them had a de novo reciprocal t(11;17) translocation. Two cases carried partially overlapping 17q24.3 duplications ~500 kb upstream of SOX9, both inherited from their normal fathers. Breakpoints cloning showed that both duplications were in tandem, whereas the 17q in the reciprocal translocation was broken at ~800 kb upstream of SOX9, which is not only close to a previously described 46,XX DSD translocation, but also to translocations without any effects on the gonadal development. A further XX male, ascertained because of intellectual disability, carried a de novo cryptic duplication at Xq27.1, involving SOX3. CNVs involving SOX3 or its flanking regions have been reported in four XX DSD subjects. Collectively in our cohort of 19 novel cases of SRY-negative 46,XX DSD, the duplications upstream of SOX9 account for ~10.5% of the cases, and are responsible for the disease phenotype, even when inherited from a normal father. Translocations interrupting this region may also affect the gonadal development, possibly depending on the chromatin context of the recipient chromosome. SOX3 duplications may substitute SRY in some XX subjects.


Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/genética , Factor de Transcripción SOX9/genética , Factores de Transcripción SOXB1/genética , Testículo/crecimiento & desarrollo , Trastornos del Desarrollo Sexual 46, XX/fisiopatología , Adulto , Puntos de Rotura del Cromosoma , Cromosomas Humanos Par 17/genética , Cromosomas Humanos X/genética , Femenino , Humanos , Recién Nacido , Masculino , Testículo/patología , Translocación Genética/genética
17.
Hum Genome Var ; 1: 14008, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-27081502

RESUMEN

The aim of this study was to identify the genetic defect that is responsible for aniridia and congenital cataracts in two Tunisian families. Sequencing of the PAX6 gene in family F1 detected a novel c.265C>T transition in exon 6. In family F2, the previously described c.718C>T mutation in PAX6 was detected in the four affected members. This study adds new mutation to those previously reported in PAX6, providing further evidence for the genetic and phenotypic heterogeneity in individuals with aniridia ocular malformations.

18.
Eur J Med Genet ; 56(1): 13-9, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23142735

RESUMEN

Intellectual Deficiency (ID) is a common neuropsychiatric disorder whose etiopathogenesis still insufficiently understood. In the last decade, several surveys, assessing epidemiologic, clinical and etiologic parameters of ID, have been performed but none of them is realized in a Tunisian population. In this retrospective survey, we propose to study these parameters, in a Tunisian cohort of 458 patients with constitutional ID, and to assess our diagnostic strategy. Data analyses, by the SPSS program, reveal a male predominance, a high level of consanguinity, an advanced mean age of patients, a rare frequentation of specialized institutions by the severely affected patients, and a high frequency of familial forms with predominance of the recessive autosomal ones. The study of clinical parameters and investigations' results shows that 72.1% of our patients present a syndromic ID. For these patients, chromosomal anomalies are rarely described, EEG anomalies were usually non-specific in patients without clinical evidence of epilepsy, and brain anomalies are common in patients with severe ID, neurological symptoms or history of seizures. Aetiology is identified in 13.1% of them whereas it is still unknown in 100% of patients with non-specific ID. This study allows us to better characterize, epidemiologically and clinically, the first large Tunisian cohort of patients with ID and to assess our diagnostic strategy in order to propose a revised one that will improve the diagnostic lead, the care chain and the preventive resources of ID.


Asunto(s)
Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/epidemiología , Adolescente , Niño , Preescolar , Consanguinidad , Electroencefalografía , Femenino , Humanos , Discapacidad Intelectual/etiología , Masculino , Fenotipo , Túnez/epidemiología
19.
Eur J Hum Genet ; 19(8): 851-6, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21559051

RESUMEN

Nance-Horan Syndrome (NHS) or X-linked cataract-dental syndrome is a disease of unknown gene action mechanism, characterized by congenital cataract, dental anomalies, dysmorphic features and, in some cases, mental retardation. We performed linkage analysis in a Tunisian family with NHS in which affected males and obligate carrier female share a common haplotype in the Xp22.32-p11.21 region that contains the NHS gene. Direct sequencing of NHS coding exons and flanking intronic sequences allowed us to identify the first missense mutation (P551S) and a reported SNP-polymorphism (L1319F) in exon 6, a reported UTR-SNP (c.7422 C>T) and a novel one (c.8239 T>A) in exon 8. Both variations P551S and c.8239 T>A segregate with NHS phenotype in this family. Although truncations, frame-shift and copy number variants have been reported in this gene, no missense mutations have been found to segregate previously. This is the first report of a missense NHS mutation causing NHS phenotype (including cardiac defects). We hypothesize also that the non-reported UTR-SNP of the exon 8 (3'-UTR) is specific to the Tunisian population.


Asunto(s)
Catarata/congénito , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Proteínas Nucleares/genética , Anomalías Dentarias/genética , Regiones no Traducidas 3' , Secuencia de Aminoácidos , Catarata/genética , Catarata/fisiopatología , Análisis Mutacional de ADN , Exones , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Cardiopatías Congénitas/genética , Humanos , Masculino , Proteínas de la Membrana , Datos de Secuencia Molecular , Mutación Missense , Linaje , Polimorfismo de Nucleótido Simple , Anomalías Dentarias/fisiopatología , Túnez
20.
Eur J Med Genet ; 54(4): e446-50, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21621018

RESUMEN

Derivatives of chromosome 15, often referred to as inv dup(15), represent the most common supernumerary marker chromosome (SMC). SMC(15)s can be classified into two major groups according to their length: small SMC(15) and large ones. Depending on the amount of euchromatin, the carriers may either present with a normal phenotype or with a recognizable syndrome. Here we describe a patient with severe mental retardation, epilepsy, dysmorphic features and pigmentary dysplasia. His karyotype was 47,XY,+mar[41]/46,XY[9]. Chromosomal fluorescence in situ hybridization (FISH) showed the SMC to be originating from chromosome 15, dicentric and containing four copies of the Prader-Willi/Angelman Syndrome Critical Region (PWACR), including the OCA2 gene. Molecular studies indicated that it is maternally derived. This report supports the previous observations assuming that severity of phenotype in patients with SMC(15) depends on the dosage of the PWACR and that skin pigmentation is correlated to OCA2 gene copy number.


Asunto(s)
Síndrome de Angelman/genética , Proteínas de Transporte de Membrana/genética , Trastornos de la Pigmentación/genética , Síndrome de Prader-Willi/genética , Adolescente , Bandeo Cromosómico , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 15/genética , Humanos , Masculino , Fenotipo
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