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1.
Neurogenetics ; 19(2): 93-103, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29511999

RESUMO

Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.


Assuntos
Deficiência Intelectual/genética , Complexo Mediador/genética , Criança , Pré-Escolar , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Mutação de Sentido Incorreto , Fenótipo
2.
Clin Genet ; 89(5): 630-5, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26582393

RESUMO

Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.


Assuntos
Hibridização Genômica Comparativa/métodos , Aconselhamento Genético/ética , Aconselhamento Genético/métodos , Achados Incidentais , Revelação/ética , Feminino , França , Genes Dominantes/genética , Genes Recessivos/genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Masculino , Análise em Microsséries/métodos , Relações Médico-Paciente/ética , Estudos Retrospectivos , Inquéritos e Questionários
3.
Clin Genet ; 86(4): 326-34, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24033328

RESUMO

Anophthalmia and microphthalmia (AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and different genes have been demonstrated to be causative of syndromic and non-syndromic forms of AM. We screened seven AM genes [GDF6 (growth differentiation factor 6), FOXE3 (forkhead box E3), OTX2 (orthodenticle protein homolog 2), PAX6 (paired box 6), RAX (retina and anterior neural fold homeobox), SOX2 (SRY sex determining region Y-box 2), and VSX2 (visual system homeobox 2 gene)] in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21% of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition eight gene deletions (five SOX2, two OTX2 and one RAX) were identified using a semi-quantitative multiplex polymerase chain reaction (PCR) [quantitative multiplex PCR amplification of short fluorescent fragments (QMPSF)]. The causative genetic defect was identified in 21% of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling.


Assuntos
Anoftalmia/genética , Heterogeneidade Genética , Microftalmia/genética , Mutação Puntual/genética , Adolescente , Adulto , Anoftalmia/diagnóstico , Anoftalmia/patologia , Criança , Pré-Escolar , Proteínas do Olho/genética , Feminino , Fatores de Transcrição Forkhead/genética , Fator 6 de Diferenciação de Crescimento/genética , Proteínas de Homeodomínio/genética , Humanos , Lactente , Masculino , Microftalmia/diagnóstico , Microftalmia/patologia , Fatores de Transcrição Otx/genética , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/genética , Proteínas Repressoras/genética , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição/genética
4.
Clin Genet ; 81(3): 265-71, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21204802

RESUMO

Prenatal diagnosis of true mosaic trisomy 7 is rare in amniotic fluid and can be misinterpreted as pseudomosaic. The phenotype is highly variable and may be modified by a maternal uniparental disomy of chromosome 7 leading to mild Russell-Silver syndrome (RSS). We report here the third postnatal case of mosaic trisomy 7 with maternal uniparental disomy of chromosome 7 in a boy presenting a mild RSS. Fetal karyotype performed in amniocentesis for intrauterine growth retardation was considered normal. Mosaic trisomy 7 was diagnosed after birth, on fibroblasts karyotype performed for blaschkolinear pigmentary skin anomalies and failure to thrive. Maternal uniparental disomy of chromosome 7 was observed in blood sample. Retrospectively, trisomic 7 cells were identified in one prenatal long-term flask culture revealing a prenatal diagnosis failure. This report emphasizes the difficulty of assessing fetal mosaicism and distinguishing it from pseudomosaicism in cultured amniocytes. It is important to search for uniparental disomy as an indirect clue of trisomy 7 mosaicism and a major prognosis element. Although there are only few prenatal informative cases, detection of trisomy 7 in amniocentesis appears to be associated with a relatively good outcome when maternal uniparental disomy has been ruled out.


Assuntos
Síndrome de Silver-Russell/diagnóstico , Trissomia/diagnóstico , Dissomia Uniparental/diagnóstico , Amniocentese , Cromossomos Humanos Par 7/genética , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Retardo do Crescimento Fetal , Humanos , Cariótipo , Masculino , Mosaicismo , Gravidez , Diagnóstico Pré-Natal , Síndrome de Silver-Russell/genética , Trissomia/genética , Dissomia Uniparental/genética
5.
Rev Chir Orthop Reparatrice Appar Mot ; 92(1): 83-94, 2006 Feb.
Artigo em Francês | MEDLINE | ID: mdl-16609623

RESUMO

Limb malformations are frequent. These malformations are isolated or associated with anomalies of other developmental fields and accurate diagnostic is essential for prognosis evaluation, treatment and genetic counseling. Animal embryology and molecular biology techniques, have given us a better understanding of the processes of growth and patterning of the limb buds. The key genes that are involved in these processes have been identified and their interactions recognized. Human genetics has been able to identify, or at least localize, several genes implicated in limb development. We here review the present knowledge on these genes and their mutations responsible for limb anomalies.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/cirurgia , Ortopedia , Extremidades/embriologia , Aconselhamento Genético , Testes Genéticos , Humanos , Prognóstico
6.
Am J Med Genet ; 76(3): 217-21, 1998 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-9508240

RESUMO

Blau syndrome (MK186580) comprises granulomatous arthritis, iritis, and skin rash, and is an autosomal-dominant trait with variable expressivity. So far it was described in 5 families. We report on a sixth family with severe progression of eye involvement and discuss the nosology with similar diseases, such as early-infantile sarcoidosis.


Assuntos
Artrite/patologia , Exantema/patologia , Granuloma/patologia , Irite/patologia , Adolescente , Adulto , Artrite/genética , Cegueira/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 16 , Exantema/genética , Feminino , Retardo do Crescimento Fetal , Genótipo , Granuloma/genética , Humanos , Lactente , Irite/genética , Masculino , Linhagem , Sarcoidose/patologia , Síndrome , Sinovite/genética , Sinovite/patologia , Gêmeos Monozigóticos
7.
Genet Couns ; 7(2): 131-4, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8831132

RESUMO

We describe a 24-weeks-old fetus with Fryns' syndrome (FS) and two erupted incisors. The present observations is another example of prenatal diagnosis of FS, based on ultrasonographically detected hernia diaphragmatica and cystic hygroma. It also adds an hitherto non described finding in FS. The presence of prenatally erupted teeth without any similar family history is discussed.


Assuntos
Aberrações Cromossômicas/embriologia , Hérnia Diafragmática/embriologia , Linfangioma Cístico/embriologia , Dentes Natais/embriologia , Erupção Dentária , Transtornos Cromossômicos , Hérnia Diafragmática/complicações , Hérnia Diafragmática/diagnóstico , Humanos , Linfangioma Cístico/complicações , Linfangioma Cístico/diagnóstico , Síndrome
8.
Genet Couns ; 7(4): 249-55, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8985728

RESUMO

The association of pelvi-ureteric junction obstruction (PUJO) and rapidly fatal persistent pulmonary hypertension of the newborn (PPHN) has been observed in two male siblings. PUJO was also observed in a maternal uncle, whose daughter suffered from vesico-ureteral reflux (VUR). In both patients, histopathologic study of the lungs showed misalignment of pulmonary veins (MAPV), which is a rare autosomal recessive condition leading to severe PPHN and death within the neonatal period. It has occasionally been described associated with PUJO. The authors point out that: i: MAPV has to be carefully searched in case of PPHN; ii: PUJO could be an important finding associated with MAPV, and the only prenatal indication of this lethal condition.


Assuntos
Hidronefrose/complicações , Hipertensão Pulmonar/complicações , Pulmão/irrigação sanguínea , Veias Pulmonares/fisiopatologia , Humanos , Hipertensão Pulmonar/fisiopatologia , Lactente , Recém-Nascido , Pulmão/fisiopatologia , Masculino , Veias Pulmonares/ultraestrutura
9.
Arch Pediatr ; 8(8): 838-42, 2001 Aug.
Artigo em Francês | MEDLINE | ID: mdl-11524915

RESUMO

UNLABELLED: Dyggve-Melchior-Clausen syndrome (DMCS) is an autosomal recessive skeletal dysplasia. Clinical and radiological similarities with Morquio's syndrome can initially lead wrongly to this diagnosis. CASE REPORT: A nine-year-old boy had mental retardation and progressive postnatal dwarfism. Platyspondyly and dysplastic epiphyses and metaphyses resembled those of Morquio's disease; however, clinical and radiological data led to the diagnosis of DMCS. CONCLUSION: Clinical and paraclinical features allowing the differentiation of Morquio's syndrome and DMCS are discussed. Initial clinical presentation may be similar, but the intellectual prognosis is different.


Assuntos
Doenças do Desenvolvimento Ósseo/diagnóstico , Nanismo/etiologia , Deficiência Intelectual/etiologia , Mucopolissacaridose IV/diagnóstico , Doenças do Desenvolvimento Ósseo/congênito , Criança , Diagnóstico Diferencial , Humanos , Masculino , Síndrome
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