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1.
Eur J Med Genet ; 66(8): 104797, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37285932

RESUMO

The SMARCC1 gene has been involved in congenital ventriculomegaly with aqueduct stenosis but only a few patients have been reported so far, with no antenatal cases, and it is currently not annotated as a morbid gene in OMIM nor in the Human Phenotype Ontology. Most of the reported variants are loss of function (LoF) and are often inherited from unaffected parents. SMARCC1 encodes a subunit of the mSWI/SNF complex and affects the chromatin structure and expression of several genes. Here, we report the two first antenatal cases of SMARCC1 LoF variants detected by Whole Genome Sequencing (WGS). Ventriculomegaly is the common feature in those fetuses. Both identified variants are inherited from a healthy parent, which supports the reported incomplete penetrance of this gene. This makes the identification of this condition in WGS as well as the genetic counseling challenging.


Assuntos
Hidrocefalia , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/genética , Feto , Aconselhamento Genético , Fatores de Transcrição/genética
2.
Cardiol Young ; 29(12): 1546-1548, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31679548

RESUMO

We report the case of a fetus with anamnios sequence and VACTERL syndrome, having a circumflex right aortic arch. Two arterial ducts join anteriorly to form a common vessel that connects to the pulmonary trunk with confluent pulmonary branches. Embryologically, the dorsal right 6th aortic arch did not disappear and the aortic arch development stopped in a symmetrical state with an exceptional "Y-shaped" merged bilateral arterial duct.


Assuntos
Canal Anal/anormalidades , Síndromes do Arco Aórtico/patologia , Esôfago/anormalidades , Cardiopatias Congênitas/patologia , Rim/anormalidades , Deformidades Congênitas dos Membros/patologia , Artéria Pulmonar/anormalidades , Artéria Pulmonar/patologia , Coluna Vertebral/anormalidades , Traqueia/anormalidades , Aborto Induzido , Adulto , Canal Anal/patologia , Síndromes do Arco Aórtico/congênito , Esôfago/patologia , Feminino , Feto , Humanos , Rim/patologia , Masculino , Coluna Vertebral/patologia , Traqueia/patologia
3.
Am J Hum Genet ; 99(4): 928-933, 2016 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-27616481

RESUMO

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through linkage analysis, homozygosity mapping, and exome sequencing in four unrelated families affected by lethal AMC, we identified biallelic mutations in GLDN in the affected individuals. GLDN encodes gliomedin, a secreted cell adhesion molecule involved in the formation of the nodes of Ranvier. Transmission electron microscopy of the sciatic nerve from one of the affected individuals showed a marked lengthening defect of the nodes. The GLDN mutations found in the affected individuals abolish the cell surface localization of gliomedin and its interaction with its axonal partner, neurofascin-186 (NF186), in a cell-based assay. The axoglial contact between gliomedin and NF186 is essential for the initial clustering of Na+ channels at developing nodes. These results indicate a major role of gliomedin in node formation and the development of the peripheral nervous system in humans. These data indicate that mutations of GLDN or CNTNAP1 (MIM: 616286), encoding essential components of the nodes of Ranvier and paranodes, respectively, lead to inherited nodopathies, a distinct disease entity among peripheral neuropathies.


Assuntos
Artrogripose/genética , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Nós Neurofibrosos/metabolismo , Alelos , Axônios/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Exoma/genética , Feminino , Morte Fetal , Humanos , Recém-Nascido , Masculino , Proteínas de Membrana/metabolismo , Fatores de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Linhagem , Ligação Proteica/genética , Nós Neurofibrosos/ultraestrutura
5.
Orphanet J Rare Dis ; 8: 106, 2013 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-23849162

RESUMO

BACKGROUND: Laminopathies, due to mutations in LMNA, encoding A type-lamins, can lead to premature ageing and/or lipodystrophic syndromes, showing that these diseases could have close physiopathological relationships. We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeria Werner syndrome linked to mutations in WRN, encoding a RecQ DNA helicase. METHODS: We analysed the clinical and biological features of two women, aged 32 and 36, referred for partial lipodystrophic syndrome which led to the molecular diagnosis of Werner syndrome. Cultured skin fibroblasts from one patient were studied. RESULTS: Two normal-weighted women presented with a partial lipodystrophic syndrome with hypertriglyceridemia and liver steatosis. One of them had also diabetes. Both patients showed a peculiar, striking lipodystrophic phenotype with subcutaneous lipoatrophy of the four limbs contrasting with truncal and abdominal fat accumulation. Their oral glucose tolerance tests showed extremely high levels of insulinemia, revealing major insulin resistance. Low serum levels of sex-hormone binding globulin and adiponectin suggested a post-receptor insulin signalling defect. Other clinical features included bilateral cataracts, greying hair and distal skin atrophy. We observed biallelic WRN null mutations in both women (p.Q748X homozygous, and compound heterozygous p.Q1257X/p.M1329fs). Their fertility was decreased, with preserved menstrual cycles and normal follicle-stimulating hormone levels ruling out premature ovarian failure. However undetectable anti-müllerian hormone and inhibin B indicated diminished follicular ovarian reserve. Insulin-resistance linked ovarian hyperandrogenism could also contribute to decreased fertility, and the two patients became pregnant after initiation of insulin-sensitizers (metformin). Both pregnancies were complicated by severe cervical incompetence, leading to the preterm birth of a healthy newborn in one case, but to a second trimester-abortion in the other. WRN-mutated fibroblasts showed oxidative stress, increased lamin B1 expression, nuclear dysmorphies and premature senescence. CONCLUSIONS: We show here for the first time that partial lipodystrophy with severe insulin resistance can reveal WRN-linked premature aging syndrome. Increased expression of lamin B1 with altered lamina architecture observed in WRN-mutated fibroblasts could contribute to premature cellular senescence. Primary alterations in DNA replication and/or repair should be considered as possible causes of lipodystrophic syndromes.


Assuntos
Exodesoxirribonucleases/genética , Resistência à Insulina/genética , Lipodistrofia/complicações , Lipodistrofia/genética , Mutação , RecQ Helicases/genética , Síndrome de Werner/complicações , Síndrome de Werner/genética , Adulto , Células Cultivadas , Senescência Celular/genética , Feminino , Fibroblastos/metabolismo , Humanos , Recém-Nascido , Lipodistrofia/fisiopatologia , Gravidez , Pele/citologia , Síndrome de Werner/diagnóstico , Helicase da Síndrome de Werner
6.
Eur J Med Genet ; 55(2): 81-90, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22226660

RESUMO

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital malformation syndrome caused by dehydrocholesterol reductase deficiency. The diagnosis is confirmed by high 7- and secondarily 8-dehydrocholesterol levels in plasma and tissues and/or by detection of biallelic mutations in the DHCR7 gene. The phenotypic spectrum of SLOS is broad, ranging from a mild phenotype combining subtle physical anomalies with behavioral and learning problems, to a perinatally lethal multiple malformations syndrome. The fetal phenotype of SLOS has been poorly described in the literature. We report a series of 10 fetuses with molecularly proven SLOS. Even in young fetuses, the facial dysmorphism appears characteristic. Genital abnormalities are rare in 46,XX subjects. Gonadal differentiation appears histologically normal and in agreement with the chromosomal sex, contrary to what has been previously stated. We observed some previously unreported anomalies: ulnar hypoplasia, vertebral segmentation anomalies, congenital pulmonary adenomatoid malformation, fused lungs, gastroschisis, holomyelia and hypothalamic hamartoma. This latter malformation proves that SLOS phenotypically overlaps with Pallister-Hall syndrome which remains clinically a major differential diagnosis of SLOS.


Assuntos
Feto/patologia , Fenótipo , Síndrome de Smith-Lemli-Opitz/patologia , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Observação
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