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2.
Prenat Diagn ; 39(10): 871-882, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31172545

RESUMO

OBJECTIVE/METHOD: 1p36 deletion syndrome is considered to be the most common deletion after 22q11.2 deletion. It is characterized by specific facial features, developmental delay, and organ defects. The primary objective of the present multicenter study was to survey all the cases of 1p36 deletion diagnosed prenatally by French cytogenetics laboratories using a chromosomal microarray. We then compared these new cases with the literature data. RESULTS: Ten new cases were reported. On average, the 1p36 deletion was diagnosed at 19 weeks of gestation. The size of the deletion ranged from 1.6 to 16 Mb. The 1p36 deletion was the only chromosomal abnormality in eight cases and was associated with a complex chromosome 1 rearrangement in the two remaining cases. The invasive diagnostic procedure had always been prompted by abnormal ultrasound findings: elevated nuchal translucency, structural brain abnormality, retrognathia, or a cardiac defect. Multiple anomalies were present in all cases. DISCUSSION: We conclude that 1p36 deletion is not associated with any specific prenatal signs. We suggest that a prenatal observation of ventriculomegaly, congenital heart defect, or facial dysmorphism should prompt the clinician to consider a diagnosis of 1p36 deletion syndrome.

3.
Prenat Diagn ; 39(6): 464-470, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896039

RESUMO

OBJECTIVES: Congenital heart defects (CHDs) may be isolated or associated with other malformations. The use of chromosome microarray (CMA) can increase the genetic diagnostic yield for CHDs by between 4% and 10%. The objective of this study was to evaluate the value of CMA after the prenatal diagnosis of an isolated CHD. METHODS: In a retrospective, nationwide study performed in France, we collected data on all cases of isolated CHD that had been explored using CMAs in 2015. RESULTS: A total of 239 fetuses were included and 33 copy number variations (CNVs) were reported; 19 were considered to be pathogenic, six were variants of unknown significance, and eight were benign variants. The anomaly detection rate was 10.4% overall but ranged from 0% to 16.7% as a function of the isolated CHD in question. The known CNVs were 22q11.21 deletions (n = 10), 22q11.21 duplications (n = 2), 8p23 deletions (n = 2), an Alagille syndrome (n = 1), and a Kleefstra syndrome (n = 1). CONCLUSION: The additional diagnostic yield was clinically significant (3.1%), even when anomalies in the 22q11.21 region were not taken into account. Hence, patients with a suspected isolated CHD and a normal karyotype must be screened for chromosome anomalies other than 22q11.21 duplications and deletions.

4.
Haematologica ; 104(8): 1554-1564, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30655378

RESUMO

We describe the clinical, hematologic and genetic characteristics of a retrospective series of 126 subjects from 64 families with hereditary xerocytosis. Twelve patients from six families carried a KCNN4 mutation, five had the recurrent p.Arg352His mutation and one had a new deletion at the exon 7-intron 7 junction. Forty-nine families carried a PIEZO1 mutation, which was a known recurrent mutation in only one-third of the cases and private sequence variation in others; 12 new probably pathogenic missense mutations were identified. The two dominant features leading to diagnosis were hemolysis that persisted after splenectomy and hyperferritinemia, with an inconstant correlation with liver iron content assessed by magnetic resonance imaging. PIEZO1-hereditary xerocytosis was characterized by compensated hemolysis in most cases, perinatal edema of heterogeneous severity in more than 20% of families and a major risk of post-splenectomy thrombotic events, including a high frequency of portal thrombosis. In KCNN4-related disease, the main symptoms were more severe anemia, hemolysis and iron overload, with no clear sign of red cell dehydration; therefore, this disorder would be better described as a 'Gardos channelopathy'. These data on the largest series to date indicate that PIEZO1-hereditary xerocytosis and Gardos channelopathy are not the same disease although they share hemolysis, a high rate of iron overload and inefficient splenectomy. They demonstrate the high variability in clinical expression as well as genetic bases of PIEZO1-hereditary xerocytosis. These results will help to improve the diagnosis of hereditary xerocytosis and to provide recommendations on the clinical management in terms of splenectomy, iron overload and pregnancy follow-up.

5.
Am J Hum Genet ; 104(2): 213-228, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639323

RESUMO

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

6.
Brain ; 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30508070

RESUMO

Holoprosencephaly is a pathology of forebrain development characterized by high phenotypic heterogeneity. The disease presents with various clinical manifestations at the cerebral or facial levels. Several genes have been implicated in holoprosencephaly but its genetic basis remains unclear: different transmission patterns have been described including autosomal dominant, recessive and digenic inheritance. Conventional molecular testing approaches result in a very low diagnostic yield and most cases remain unsolved. In our study, we address the possibility that genetically unsolved cases of holoprosencephaly present an oligogenic origin and result from combined inherited mutations in several genes. Twenty-six unrelated families, for whom no genetic cause of holoprosencephaly could be identified in clinical settings [whole exome sequencing and comparative genomic hybridization (CGH)-array analyses], were reanalysed under the hypothesis of oligogenic inheritance. Standard variant analysis was improved with a gene prioritization strategy based on clinical ontologies and gene co-expression networks. Clinical phenotyping and exploration of cross-species similarities were further performed on a family-by-family basis. Statistical validation was performed on 248 ancestrally similar control trios provided by the Genome of the Netherlands project and on 574 ancestrally matched controls provided by the French Exome Project. Variants of clinical interest were identified in 180 genes significantly associated with key pathways of forebrain development including sonic hedgehog (SHH) and primary cilia. Oligogenic events were observed in 10 families and involved both known and novel holoprosencephaly genes including recurrently mutated FAT1, NDST1, COL2A1 and SCUBE2. The incidence of oligogenic combinations was significantly higher in holoprosencephaly patients compared to two control populations (P < 10-9). We also show that depending on the affected genes, patients present with particular clinical features. This study reports novel disease genes and supports oligogenicity as clinically relevant model in holoprosencephaly. It also highlights key roles of SHH signalling and primary cilia in forebrain development. We hypothesize that distinction between different clinical manifestations of holoprosencephaly lies in the degree of overall functional impact on SHH signalling. Finally, we underline that integrating clinical phenotyping in genetic studies is a powerful tool to specify the clinical relevance of certain mutations.

7.
Genet Med ; 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30190612

RESUMO

PURPOSE: To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants. METHODS: We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants. RESULTS: The number of rare likely deleterious variants in functionally intolerant genes ("other hits") correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. CONCLUSION: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.

8.
Eur J Hum Genet ; 26(12): 1784-1790, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30135486

RESUMO

X-linked dominant chondrodysplasia punctata (CDPX2 or Conradi-Hünermann-Happle syndrome, MIM #302960) is caused by mutations in the EBP gene. Affected female patients present with Blaschkolinear ichthyosis, coarse hair or alopecia, short stature, and normal psychomotor development. The disease is usually lethal in boys. Nevertheless, few male patients have been reported; they carry a somatic mosaicism in EBP or present with Klinefelter syndrome. Here, we report CDPX2 patients belonging to a three-generation family, carrying the splice variant c.301 + 5 G > C in intron 2 of EBP. The grandfather carries the variant as mosaic state and presents with short stature and mild ichthyosis. The mother also presents with short stature and mild ichthyosis and the female fetus with severe limb and vertebrae abnormalities and no skin lesions, with random X inactivation in both. This further characterizes the phenotypical spectrum of CDPX2, as well as intrafamilial variability, and raises the question of differential EBP mRNA splicing between the different target tissues.

9.
Nature ; 561(7722): E7, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29977062

RESUMO

In this Letter, the surname of author Lena Vlaminck was misspelled 'Vlaeminck'. In addition, author Kris Vleminckx should have been associated with affiliation 16 (Center for Medical Genetics, Ghent University, Ghent, Belgium). These have been corrected online.

10.
Nature ; 557(7706): 564-569, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29769720

RESUMO

The four R-spondin secreted ligands (RSPO1-RSPO4) act via their cognate LGR4, LGR5 and LGR6 receptors to amplify WNT signalling1-3. Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs. Functional studies revealed impaired binding to the LGR4/5/6 receptors and the RNF43 and ZNRF3 transmembrane ligases, and reduced WNT potentiation, which correlated with allele severity. Unexpectedly, however, the triple and ubiquitous knockout of Lgr4, Lgr5 and Lgr6 in mice did not recapitulate the known Rspo2 or Rspo3 loss-of-function phenotypes. Moreover, endogenous depletion or addition of exogenous RSPO2 or RSPO3 in triple-knockout Lgr4/5/6 cells could still affect WNT responsiveness. Instead, we found that the concurrent deletion of rnf43 and znrf3 in Xenopus embryos was sufficient to trigger the outgrowth of supernumerary limbs. Our results establish that RSPO2, without the LGR4/5/6 receptors, serves as a direct antagonistic ligand to RNF43 and ZNRF3, which together constitute a master switch that governs limb specification. These findings have direct implications for regenerative medicine and WNT-associated cancers.


Assuntos
Proteínas de Ligação a DNA/antagonistas & inibidores , Extremidades/embriologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Deformidades Congênitas dos Membros/genética , Receptores Acoplados a Proteínas-G/metabolismo , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Animais , Proteínas de Ligação a DNA/metabolismo , Feminino , Fibroblastos , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Camundongos , Proteínas Oncogênicas/antagonistas & inibidores , Proteínas Oncogênicas/metabolismo , Fenótipo , Receptores Acoplados a Proteínas-G/deficiência , Ubiquitina-Proteína Ligases/metabolismo , Xenopus/genética
12.
Fetal Pediatr Pathol ; 37(6): 387-399, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30633605

RESUMO

OBJECTIVES: To evaluate the frequency of placental pathological lesions in Beckwith-Wiedemann syndrome (BWS), an overgrowth disorder that exhibits etiologic molecular heterogeneity and variable phenotypic expression. MATERIALS AND METHODS: The study included 60 BWS patients with a proven molecular diagnosis and a placental pathological examination. Placentomegaly, placental mesenchymal dysplasia (PMD), chorangioma/chorangiomatosis, and extravillous trophoblastic (EVT) cytomegaly were evaluated and their frequencies in the different molecular subgroups were compared. Immunohistochemistry and fluorescent in situ hybridization (FISH) were performed on EVT cytomegaly. RESULTS: Placentomegaly was found in 70.9% of cases, PMD in 21.7%, chorangioma/chorangiomatosis in 23.3%, and EVT cytomegaly in 21.7%; there was no significant intergroup difference. EVT cytomegaly showed loss of p57 expression, increased Ki67 proliferating index, and polyploidy on FISH analysis. CONCLUSIONS: There was no genotype/epigenotype-phenotype correlation concerning placental lesions in BWS. Diffuse EVT cytomegaly with polyploidy may represent a placental finding suggestive of BWS.


Assuntos
Síndrome de Beckwith-Wiedemann/genética , Síndrome de Beckwith-Wiedemann/patologia , Placenta/patologia , Adulto , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Gravidez , Estudos Retrospectivos
13.
NPJ Genom Med ; 2: 32, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29263841

RESUMO

Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inherited SHANK3 deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.

14.
Brain ; 140(10): 2597-2609, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28969387

RESUMO

Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.


Assuntos
Fibroblastos/citologia , Microcefalia/genética , Microcefalia/patologia , Mitose/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Células-Tronco Neurais/citologia , Animais , Animais Geneticamente Modificados , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Células Cultivadas , Pré-Escolar , Drosophila , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Feminino , Fibroblastos/patologia , Regulação da Expressão Gênica/genética , Humanos , Antígeno Ki-67/metabolismo , Masculino , Microcefalia/diagnóstico por imagem , Células-Tronco Neurais/patologia , Interferência de RNA/fisiologia , Adulto Jovem
15.
Eur J Hum Genet ; 25(8): 930-934, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28612834

RESUMO

Sex chromosome aneuploidies (SCA) is a group of conditions in which individuals have an abnormal number of sex chromosomes. SCA, such as Klinefelter's syndrome, XYY syndrome, and Triple X syndrome are associated with a large range of neurological outcome. Another genetic event such as another cytogenetic abnormality may explain a part of this variable expressivity. In this study, we have recruited fourteen patients with intellectual disability or developmental delay carrying SCA associated with a copy-number variant (CNV). In our cohort (four patients 47,XXY, four patients 47,XXX, and six patients 47,XYY), seven patients were carrying a pathogenic CNV, two a likely pathogenic CNV and five a variant of uncertain significance. Our analysis suggests that CNV might be considered as an additional independent genetic factor for intellectual disability and developmental delay for patients with SCA and neurodevelopmental disorder.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Transtornos dos Cromossomos Sexuais/genética , Trissomia/genética , Cariótipo XYY/genética , Cromossomos Humanos X/genética , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/diagnóstico , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Fenótipo , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/diagnóstico , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/diagnóstico , Trissomia/diagnóstico , Cariótipo XYY/diagnóstico
16.
Eur J Hum Genet ; 25(1): 150-152, 2016 01.
Artigo em Inglês | MEDLINE | ID: mdl-27782105

RESUMO

Homozygous frameshift variants in CNTNAP1 have recently been reported in patients with arthrogryposis and abnormal axon myelination. In two brothers with severe congenital hypotonia and foot deformities, we identified compound heterozygous variants in CNTNAP1, reporting the first causative missense variant, p.(Cys323Arg). Motor nerve conductions were markedly decreased. Nerve microscopical lesions confirmed a severe hypomyelinating process and showed loss of attachment sites of the myelin loops on the axons, which could be a characteristic of Caspr loss-of-function. We discuss the pathophysiology of the myelination process and we propose to consider this disorder as a congenital hypomyelinating neuropathy.


Assuntos
Artrogripose/genética , Moléculas de Adesão Celular Neuronais/genética , Deformidades do Pé/genética , Hipotonia Muscular/genética , Artrogripose/fisiopatologia , Deformidades do Pé/fisiopatologia , Predisposição Genética para Doença , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Hipotonia Muscular/fisiopatologia , Mutação de Sentido Incorreto , Bainha de Mielina/genética , Irmãos
17.
Prenat Diagn ; 36(8): 744-51, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27297286

RESUMO

OBJECTIVES: To describe macroscopic and microscopic anomalies present in fetuses carrying hepatocyte nuclear factor-1 ß mutation, their frequency, and genotype/phenotype correlations. METHODS: Clinical data, ultrasound findings, genetic studies, and autopsy reports of 20 fetal autopsies were analyzed. Histology was reviewed by two pathologists. RESULTS: Macroscopic findings were typically unilateral or bilateral renal enlargement and cortical cysts. Renal lesions were associated with congenital anomalies of the kidney and urinary tract in 25% of cases. Microscopic renal anomalies were dominated by glomerulocystic kidney and renal dysplasia. Extra-renal manifestations such as pancreatic hypoplasia (75%) and genital anomalies (68%) were only detected at autopsy. In 40% of cases, there was heterozygous deletion of the whole gene. There were de novo mutations in 40%. CONCLUSION: This study underlines the importance of considering hepatocyte nuclear factor-1 ß mutations in fetuses with congenital anomalies of the kidney and urinary tract, especially when associated with pancreatic hypoplasia. No correlation between phenotype and genotype was found, highlighting high intra-familial variability in cases with inherited mutations. © 2016 John Wiley & Sons, Ltd.


Assuntos
Fator 1-beta Nuclear de Hepatócito/genética , Rim/anormalidades , Pâncreas/anormalidades , Pancreatopatias/congênito , Anormalidades Urogenitais/genética , Autopsia , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/genética , Anormalidades Congênitas/patologia , Feminino , Genótipo , Humanos , Rim/diagnóstico por imagem , Rim/patologia , Masculino , Mutação , Pâncreas/diagnóstico por imagem , Pancreatopatias/diagnóstico por imagem , Pancreatopatias/genética , Fenótipo , Gravidez , Ultrassonografia Pré-Natal , Anormalidades Urogenitais/diagnóstico por imagem , Anormalidades Urogenitais/patologia
18.
Prenat Diagn ; 35(1): 35-43, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25118001

RESUMO

OBJECTIVE: Microduplication 22q11.2 is primarily characterized by a highly variable clinical phenotype, which ranges from apparently normal or slightly dysmorphic features (in the presence or absence of learning disorders) to severe malformations with profound mental retardation. Hence, genetic counseling is particularly challenging when microduplication 22q11.2 is identified in a prenatal diagnosis. Here, we report on 24 prenatal cases of microduplication 22q11.2. METHODS: Seventeen of the cases were also reanalyzed by microarray analysis, in order to determine copy number variations (CNVs, which are thought to influence expressivity). We also searched for possible correlations between fetal phenotypes, indications for invasive prenatal diagnosis, inheritance, and pregnancy outcomes. RESULTS: Of the 24 cases, 15 were inherited, six occurred de novo, and three were of unknown origin. Termination of pregnancy occurred in seven cases and was mainly decided on the basis of ultrasound findings. Moreover, additional CNVs were found in some patients and we try to make a genotype-phenotype correlation. CONCLUSION: We discuss the complexity of genetic counseling for microduplication 22q11.2 and comment on possible explanations for the clinical heterogeneity of this syndrome. In particular, we assessed the co-existence of additional CNVs and their contribution to phenotypic variations in chromosome 22q11.2 microduplication syndrome.


Assuntos
Anormalidades Múltiplas/diagnóstico , Síndrome de DiGeorge/diagnóstico , Estudos de Associação Genética , Diagnóstico Pré-Natal/métodos , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 22/genética , Estudos de Coortes , Hibridização Genômica Comparativa , Análise Citogenética , Síndrome de DiGeorge/epidemiologia , Síndrome de DiGeorge/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Gravidez , Resultado da Gravidez/epidemiologia
19.
Hum Mol Genet ; 23(9): 2279-89, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24319099

RESUMO

Non-syndromic arthrogryposis multiplex congenita (AMC) is characterized by multiple congenital contractures resulting from reduced fetal mobility. Genetic mapping and whole exome sequencing (WES) were performed in 31 multiplex and/or consanguineous undiagnosed AMC families. Although this approach identified known AMC genes, we here report pathogenic mutations in two new genes. Homozygous frameshift mutations in CNTNAP1 were found in four unrelated families. Patients showed a marked reduction in motor nerve conduction velocity (<10 m/s) and transmission electron microscopy (TEM) of sciatic nerve in the index cases revealed severe abnormalities of both nodes of Ranvier width and myelinated axons. CNTNAP1 encodes CASPR, an essential component of node of Ranvier domains which underlies saltatory conduction of action potentials along the myelinated axons, an important process for neuronal function. A homozygous missense mutation in adenylate cyclase 6 gene (ADCY6) was found in another family characterized by a lack of myelin in the peripheral nervous system (PNS) as determined by TEM. Morpholino knockdown of the zebrafish orthologs led to severe and specific defects in peripheral myelin in spite of the presence of Schwann cells. ADCY6 encodes a protein that belongs to the adenylate cyclase family responsible for the synthesis of cAMP. Elevation of cAMP can mimic axonal contact in vitro and upregulates myelinating signals. Our data indicate an essential and so far unknown role of ADCY6 in PNS myelination likely through the cAMP pathway. Mutations of genes encoding proteins of Ranvier domains or involved in myelination of Schwann cells are responsible for novel and severe human axoglial diseases.


Assuntos
Adenilil Ciclases/genética , Artrogripose/genética , Artrogripose/patologia , Moléculas de Adesão Celular Neuronais/genética , Axônios/patologia , Axônios/ultraestrutura , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Microscopia Eletrônica de Transmissão , Mutação/genética , Bainha de Mielina/patologia , Sistema Nervoso Periférico/patologia , Sistema Nervoso Periférico/ultraestrutura , Gravidez , Células de Schwann/metabolismo
20.
Am J Med Genet A ; 161A(6): 1436-41, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23613342

RESUMO

Telomeric associations (TAs) are fusions between two telomeres of two different chromosomes without visible loss of chromosomal material. Constitutional telomeric associations are rare chromosomal anomalies. We report on the cytogenetic and molecular analyses of a TA involving chromosomes Y and 7 in a child with a female phenotype. Prenatal cytogenetic analysis showed a 45,X chromosome complement in all cells. No fetal abnormality was identified at ultrasound examinations and the pregnancy went to term. During childhood, the proband had gonadal dysgenesis but no other phenotypic manifestations of Turner syndrome. Molecular genetic analyses showed the presence of genomic DNA of the SRY gene without any mutation. Karyotyping and fluorescent in situ hybridization (FISH) analyses on blood showed two cell lines: one cell line with a TA involving chromosomes Y and 7 [46,X,tas(Y;7)(p11.32;q36.3)] and a second cell line with a 45,X pattern. A human pantelomeric repeat TTAGGG probe hybridized to the junction of the TA within the derivative chromosome. FISH and array comparative genomic hybridization (aCGH) analyses demonstrated that tas(Y;7) occurred without detectable loss of any sequence at the derivative chromosome. SNP array analysis excluded an uniparental isodisomy of chromosome 7. Knowing more about TAs will help geneticists to deliver accurate genetic counseling.


Assuntos
Cromossomos Humanos Par 7/genética , Cromossomos Humanos Y/genética , Disgenesia Gonadal/genética , Aberrações dos Cromossomos Sexuais , Telômero/genética , Linhagem Celular , Criança , Bandeamento Cromossômico , Hibridização Genômica Comparativa , Feminino , Disgenesia Gonadal/diagnóstico , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Linfócitos/citologia , Mosaicismo , Fenótipo , Gravidez
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