Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 15 de 15
Filtrar
Mais filtros










Tipo de estudo
Intervalo de ano de publicação
1.
Eur J Hum Genet ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685998

RESUMO

Tatton-Brown-Rahman (TBRS) syndrome is a recently described overgrowth syndrome caused by loss of function variants in the DNMT3A gene. This gene encodes for a DNA methyltransferase 3 alpha, which is involved in epigenetic regulation, especially during embryonic development. Somatic variants in DNMT3A have been widely studied in different types of tumors, including acute myeloid leukemia, hematopoietic, and lymphoid cancers. Germline gain-of-function variants in this gene have been recently implicated in microcephalic dwarfism. Common clinical features of patients with TBRS include tall stature, macrocephaly, intellectual disability (ID), and a distinctive facial appearance. Differential diagnosis of TBRS comprises Sotos, Weaver, and Malan Syndromes. The majority of these disorders present other clinical features with a high clinical overlap, making necessary a molecular confirmation of the clinical diagnosis. We here describe seven new patients with variants in DNMT3A, four of them with neuropsychiatric disorders, including schizophrenia and psychotic behavior. In addition, one of the patients has developed a brain tumor in adulthood. This patient has also cerebral atrophy, aggressive behavior, ID, and abnormal facial features. Clinical evaluation of this group of patients should include a complete neuropsychiatric assessment together with psychological support in order to detect and manage abnormal behaviors such as aggressiveness, impulsivity, and attention deficit-hyperactivity disorder. TBRS should be suspected in patients with overgrowth, ID, tall stature, and macrocephaly, who also have some neuropsychiatric disorders without any genetic defects in the commonest overgrowth disorders. Molecular confirmation in these patients is mandatory.

2.
Clin Genet ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31600839

RESUMO

Aymé-Gripp syndrome (AYGRPS) is a recognizable condition caused by a restricted spectrum of dominantly acting missense mutations affecting the transcription factor MAF. Major clinical features of AYGRPS include congenital cataracts, sensorineural hearing loss, intellectual disability, and a distinctive flat facial appearance. Skeletal abnormalities have also been observed in affected individuals, even though these features have not been assessed systematically. Expanding the series with four additional patients, here we provide a more accurate delineation of the molecular aspects and clinical phenotype, particularly focusing on the skeletal features characterizing this disorder. Apart from previously reported malar flattening and joint limitations, we document that carpal/tarsal and long bone defects, and hip dysplasia occur in affected subjects more frequently than formerly appreciated.

3.
Genet Med ; 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31316167

RESUMO

PURPOSE: Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing. METHODS: In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups. RESULTS: The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups. CONCLUSIONS: Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.

4.
Eur J Med Genet ; 2018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-30006058

RESUMO

PRMT7 encodes for an arginine methyltransferase that methylates arginine residues on various protein substrates and has been shown to play a role in various developmental processes. Mutations in PRMT7 have been recently shown to be implicated in a phenotype with intellectual disability, short stature and brachydactyly, and considered to be a phenocopy of pseudohypoparathyroidism. We report a patient with short stature, psychomotor delay, hearing loss and brachydactyly, for whom whole exome sequencing detected two mutations in PRMT7 and parental segregation studies detected biallelic mutation inheritance. Few patients with biallelic PRMT7 mutations have been reported so far in the literature. We report a new patient and review all reported cases to date to delineate the clinical manifestations that may help in diagnosis this disorder, known as Short Stature, Brachydactyly, Intellectual Developmental Disability, and Seizures syndrome, allowing appropriate management and genetic counselling.

5.
Eur J Med Genet ; 61(5): 269-272, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29307792

RESUMO

The transcription factor SOX18 has been shown to play a role in the development of hair, blood and lymphatic vessels. Mutations in SOX18 result in hereditary lymphedema, with the unique clinical association of hypotrichosis and telangiectasia (HLTS). Some patients present with additional disease features which may be explained by the location of SOX18 mutation. We report a patient with hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) confirmed by detection of a novel mutation in the SOX18 gene. Few cases of HTLS have been reported in the literature. We reviewed all cases reported to date to delineate the clinical manifestations that allow us to prompt diagnosis of this syndrome for appropriate management and genetic counseling.


Assuntos
Hipotricose/genética , Linfedema/genética , Fatores de Transcrição SOXF/genética , Telangiectasia/genética , Pré-Escolar , Humanos , Hipotricose/patologia , Linfedema/patologia , Masculino , Mutação , Síndrome , Telangiectasia/patologia
6.
Eur J Med Genet ; 60(10): 517-520, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28711742

RESUMO

Microcephaly with simplified gyration, epilepsy and permanent neonatal diabetes syndrome (MEDS) is a recently described, autosomal recessive-inherited syndrome. We report the case of an infant presenting with lethargy at age five weeks and clinical findings of persistent hyperglycaemia and microcephaly with simplified gyration, suggestive of MEDS. The diagnosis was confirmed by the detection of a known c.233 T > C mutation in the IER3IP1 gene. Only eight cases of MEDS have been reported in the literature. We reviewed these with the aim of better delineating their clinical manifestations, which should allow earlier and more accurate diagnosis and genetic counseling.


Assuntos
Proteínas de Transporte/genética , Diabetes Mellitus/genética , Epilepsia/genética , Proteínas de Membrana/genética , Microcefalia/genética , Diabetes Mellitus/diagnóstico , Epilepsia/diagnóstico , Humanos , Lactente , Masculino , Microcefalia/diagnóstico , Mutação Puntual , Síndrome
7.
Eur J Med Genet ; 60(6): 303-307, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28344185

RESUMO

Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized mainly by cardiovascular, craniofacial and skeletal features. We report on a patient with LDS, whose prenatal examination was compatible with the diagnosis of arthrogryposis multiplex congenita. Neonatal assessment showed craniofacial and cardiovascular findings suggestive of LDS whose diagnosis was confirmed by the detection of a novel mutation (HGVN: NM_003242.5 (TGFBR2): c.1381T > C (p.(Cys461Arg))) in the TGFBR2 gene. Few prenatal and neonatal cases of LDS have been reported in the literature. We reviewed all cases reported to date with perinatal onset to delineate the clinical manifestations that allow us to prompt diagnosis of this syndrome at an early stage to prevent fatal cardiovascular complications. Furthermore we discuss the multidisciplinary follow up required in these patients.


Assuntos
Artrogripose/genética , Síndrome de Loeys-Dietz/genética , Mutação de Sentido Incorreto , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Artrogripose/diagnóstico , Feminino , Humanos , Recém-Nascido , Síndrome de Loeys-Dietz/diagnóstico , Receptor do Fator de Crescimento Transformador beta Tipo II
8.
Eur J Hum Genet ; 24(12): 1783-1791, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27406248

RESUMO

Variants in the ZIC3 gene are rare, but have demonstrated their profound clinical significance in X-linked heterotaxy, affecting in particular male patients with abnormal arrangement of thoracic and visceral organs. Several reports have shown relevance of ZIC3 gene variants in both familial and sporadic cases and with a predominance of mutations detected in zinc-finger domains. No studies so far have assessed the functional consequences of ZIC3 variants in an in vivo model organism. A study population of 348 patients collected over more than 10 years with a large variety of congenital heart disease including heterotaxy was screened for variants in the ZIC3 gene. Functional effects of three variants were assessed both in vitro and in vivo in the zebrafish. We identified six novel pathogenic variants (1,7%), all in either male patients with heterotaxy (n=5) or a female patient with multiple male deaths due to heterotaxy in the family (n=1). All variants were located within the zinc-finger domains or leading to a truncation before these domains. Truncating variants showed abnormal trafficking of mutated ZIC3 proteins, whereas the missense variant showed normal trafficking. Overexpression of wild-type and mutated ZIC protein in zebrafish showed full non-functionality of the two frame-shift variants and partial activity of the missense variant compared with wild-type, further underscoring the pathogenic character of these variants. Concluding, we greatly expanded the number of causative variants in ZIC3 and delineated the functional effects of three variants using in vitro and in vivo model systems.


Assuntos
Dextrocardia/genética , Deleção de Genes , Doenças Genéticas Ligadas ao Cromossomo X/genética , Síndrome de Heterotaxia/genética , Proteínas de Homeodomínio/genética , Mutação de Sentido Incorreto , Fatores de Transcrição/genética , Animais , Dextrocardia/diagnóstico , Feminino , Feto/patologia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Células HeLa , Síndrome de Heterotaxia/diagnóstico , Proteínas de Homeodomínio/metabolismo , Humanos , Recém-Nascido , Masculino , Gravidez , Transporte Proteico , Fatores de Transcrição/metabolismo , Peixe-Zebra
9.
J Natl Cancer Inst ; 108(2)2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26582061

RESUMO

BACKGROUND: Recent guidelines recommend the Lynch Syndrome prediction models MMRPredict, MMRPro, and PREMM1,2,6 for the identification of MMR gene mutation carriers. We compared the predictive performance and clinical usefulness of these prediction models to identify mutation carriers. METHODS: Pedigree data from CRC patients in 11 North American, European, and Australian cohorts (6 clinic- and 5 population-based sites) were used to calculate predicted probabilities of pathogenic MLH1, MSH2, or MSH6 gene mutations by each model and gene-specific predictions by MMRPro and PREMM1,2,6. We examined discrimination with area under the receiver operating characteristic curve (AUC), calibration with observed to expected (O/E) ratio, and clinical usefulness using decision curve analysis to select patients for further evaluation. All statistical tests were two-sided. RESULTS: Mutations were detected in 539 of 2304 (23%) individuals from the clinic-based cohorts (237 MLH1, 251 MSH2, 51 MSH6) and 150 of 3451 (4.4%) individuals from the population-based cohorts (47 MLH1, 71 MSH2, 32 MSH6). Discrimination was similar for clinic- and population-based cohorts: AUCs of 0.76 vs 0.77 for MMRPredict, 0.82 vs 0.85 for MMRPro, and 0.85 vs 0.88 for PREMM1,2,6. For clinic- and population-based cohorts, O/E deviated from 1 for MMRPredict (0.38 and 0.31, respectively) and MMRPro (0.62 and 0.36) but were more satisfactory for PREMM1,2,6 (1.0 and 0.70). MMRPro or PREMM1,2,6 predictions were clinically useful at thresholds of 5% or greater and in particular at greater than 15%. CONCLUSIONS: MMRPro and PREMM1,2,6 can well be used to select CRC patients from genetics clinics or population-based settings for tumor and/or germline testing at a 5% or higher risk. If no MMR deficiency is detected and risk exceeds 15%, we suggest considering additional genetic etiologies for the cause of cancer in the family.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/complicações , Proteínas de Ligação a DNA/genética , Heterozigoto , Proteína 2 Homóloga a MutS/genética , Mutação , Proteínas Nucleares/genética , Adulto , Idoso , Área Sob a Curva , Austrália/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Proteína 1 Homóloga a MutL , América do Norte/epidemiologia , Linhagem , Valor Preditivo dos Testes , Prevalência , Curva ROC
12.
Clin Chim Acta ; 437: 88-92, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25046559

RESUMO

BACKGROUND: Non-syndromic aortic disease (NSAD) is a frequently asymptomatic but potentially lethal disease characterised by familial cases of thoracic aortic aneurysms and dissections. This monogenic but genetically heterogeneous condition is primarily inherited as an autosomal dominant disorder with low penetrance and variable expression. Mutations in ACTA2, TGFBR1, TGFBR2, MYH11, SMAD3, MYLK, and FBN1 genes have been described but still, there are many unresolved familial cases. METHODS: The whole exome of two distantly related and affected members of a Spanish family with multiple cases of NSAD was analysed through 5500 SOLiD(™) System for the identification of shared and putative pathogenic variants. RESULTS: A new mutation termed c.C1042T:p.R348C (NM_001135599.2) was identified in TGFB2, a gene located in an evolutionary highly conserved region (Chr1: 218,519,577-218,617,961) that has been recently connected to this disease. The analysis of other family members using capillary sequencing confirmed cosegregation of the mutation with the disease and its incomplete penetrance. CONCLUSIONS: The repeated implication of TGFB2 in the development of thoracic aortic aneurysms and dissections suggests that this gene should be considered during genetic diagnosis of this disease. An accurate diagnosis of affected individuals and additional family members at risk allows for a personalised and more efficient gene-based follow-up and treatment. Finally, the reiterative presence of common musculoskeletal and craniofacial additional features in patients with TGFB2 mutations suggests the existence of a new yet undefined connective tissue syndrome responsible for not only aortic dilation, but also for the other extracardiac alterations present in the affected patients.


Assuntos
Aneurisma Dissecante/genética , Aneurisma da Aorta Torácica/genética , Mutação/genética , Análise de Sequência de DNA , Fator de Crescimento Transformador beta2/genética , Adulto , Aneurisma Dissecante/diagnóstico , Aneurisma da Aorta Torácica/diagnóstico , Criança , Exoma , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Análise de Sequência de DNA/métodos , Adulto Jovem
13.
Breast Cancer Res Treat ; 139(2): 597-602, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23624750

RESUMO

Neurofibromatosis type 1 (NF1) is a common dominant autosomal disorder caused by mutations in the NF1 gene. The main manifestations of NF1 are café-au-lait spots, neurofibromas, intertriginous freckling, Lisch nodules, and malignancy, including peripheral nerve sheath tumors, central nervous system gliomas, and a variety of other tumors not so clearly defined. The association between NF1 and breast cancer or other gynecologic malignancies seems uncommon and has been scarcely referred in the literature. We describe a family with two females affected by both NF1 and early-onset breast cancer, and a male with NF1. We evaluated whether the concomitance of both disorders could be attributed to a NF1 mutation and its supposed increased risk of breast cancer or to the concurrence of two NF1 and BRCA1/2 germline mutations. Mutation analyses identified a frameshift mutation in BRCA1 and a nonsense mutation in NF1. Our findings stress the importance of considering all phenotypic features in families with both NF1 and breast tumors. To offer a specific risk assessment and management of both conditions, NF1 and BRCA1/2 cancer predisposing genes should be analyzed.


Assuntos
Neoplasias da Mama/complicações , Neoplasias da Mama/genética , Genes BRCA1 , Genes da Neurofibromatose 1 , Mutação em Linhagem Germinativa , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Adulto , Idade de Início , Neoplasias da Mama/diagnóstico , Mapeamento Cromossômico , Análise Mutacional de DNA , Feminino , Haplótipos , Humanos , Masculino , Neurofibromatose 1/diagnóstico , Linhagem
14.
Hum Mutat ; 34(6): 860-3, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23483706

RESUMO

The hereditary spastic paraplegias (HSPs), a group of neurodegenerative movement disorders, are among the genetically most heterogeneous clinical conditions. Still, the more than 50 forms known so far apparently explain less than 80% of cases. The present study identified two large HSP families, which seemed to show an autosomal recessive and an X-linked inheritance pattern. A set of genetic analyses including exome sequencing revealed plausible mutations only when assuming incomplete/sex-dependent penetrance of adjacent alterations in the autosomal dominant HSP gene ATL1 (c.1243C>T and c.1244G>A, respectively). By screening of additional HSP patients for the presence of these alterations, we identified three more cases and obtained additional evidence for reduced penetrance. Bisulfate sequencing and haplotype analysis indicated that c.1243C and c.1244G constitute a mutational hotspot. Our findings suggest that misinterpretation of inheritance patterns and, consequently, misselection of candidate genes to be screened in gene-focused approaches contribute to the apparently missing heritability in HSP and, potentially, in other genetically heterogeneous disorders.


Assuntos
Proteínas de Ligação ao GTP/genética , Genes Dominantes , Genes Ligados ao Cromossomo X , Proteínas de Membrana/genética , Mutação , Linhagem , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genética , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Feminino , Proteínas de Ligação ao GTP/química , Humanos , Masculino , Proteínas de Membrana/química , Dados de Sequência Molecular , Alinhamento de Sequência
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA