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1.
Hum Mutat ; 40(9): 1346-1363, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31209962

RESUMO

Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low-cost next-generation sequencing gene panel that has been transferred into clinical practice, replacing single disease-gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease-gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%. Our data also support the pathogenic role of genes recently proposed to be involved in ASD. Although many of the identified variants need further investigation to be considered disease-causing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.

2.
Mol Genet Genomic Med ; 7(5): e587, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30916491

RESUMO

BACKGROUND: Inherited epimutations of Mismatch Repair (MMR) genes are responsible for Lynch Syndrome (LS) in a small, but well defined, subset of patients. Methylation of the MSH2 promoter consequent to the deletion of the upstream EPCAM gene is found in about 1%-3% of the LS patients and represents a classical secondary, constitutional and tissue-specific epimutation. Several different EPCAM deletions have been reported worldwide, for the most part representing private variants caused by an Alu-mediated recombination. METHODS: 712 patients with suspected LS were tested for MMR mutation in our Institute. EPCAM deletions were detected by multiplex ligation-dependent probe amplification (MLPA) and then defined by Long-Range polymerase chain reaction (PCR)/Sanger sequencing. A comprehensive molecular characterization of colorectal cancer (CRC) tissues was carried out by immunohistochemistry of MMR proteins, Microsatellite Instability (MSI) assay, methylation specific MLPA and transcript analyses. In addition, somatic deletions and/or variants were investigated by MLPA and next generation sequencing (NGS). RESULTS: An EPCAM deletion was found in five unrelated probands in Italy: variants c.556-490_*8438del and c.858+1193_*5826del are novel; c.859-1430_*2033del and c.859-670_*530del were previously reported. All probands were affected by CRC at young age; tumors showed MSI and abnormal MSH2/MSH6 proteins expression. MSH2 promoter methylation, as well as aberrant in-frame or out-of-frame EPCAM/MSH2 fusion transcripts, were detected in CRCs and normal mucosae. CONCLUSION: An EPCAM deletion was the causative variant in about 2% of our institutional series of 224 LS patients, consistent with previously estimated frequencies. Early age and multiple CRCs was the main clinical feature of this subset of patients.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Molécula de Adesão da Célula Epitelial/genética , Deleção de Genes , Frequência do Gene , Adulto , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Fenótipo
4.
Genet Med ; 20(9): 965-975, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29300384

RESUMO

PURPOSE: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS. METHODS: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. RESULTS: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. CONCLUSION: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.

5.
Birth Defects Res ; 110(4): 382-389, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29193896

RESUMO

BACKGROUND: OFD1 syndrome is a rare ciliopathy inherited on a dominant X-linked mode, typically lethal in males in the first or second trimester of pregnancy. It is characterized by oral cavity and digital anomalies possibly associated with cerebral and renal signs. Its prevalence is between 1/250,000 and 1/50,000 births. It is due to heterozygous mutations of OFD1 and mutations are often de novo (75%). Familial forms show highly variable phenotypic expression. OFD1 encodes a protein involved in centriole growth, distal appendix formation, and ciliogenesis. CASES: We report the investigation of three female fetuses in which corpus callosum agenesis was detected by ultrasound during the second trimester of pregnancy. In all three fetuses, fetopathological examination allowed the diagnosis of OFD1 syndrome, which was confirmed by molecular analysis. CONCLUSIONS: To our knowledge, these are the first case reports of antenatal diagnosis of OFD1 syndrome in the absence of familial history, revealed following detection of agenesis of the corpus callosum. They highlight the impact of fetal examination following termination of pregnancy for brain malformations. They also highlight the contribution of ciliary genes to corpus callosum development.


Assuntos
Agenesia do Corpo Caloso/diagnóstico por imagem , Feto/diagnóstico por imagem , Síndromes Orofaciodigitais/diagnóstico por imagem , Ultrassonografia Pré-Natal , Feminino , Humanos , Gravidez
6.
Eur J Med Genet ; 61(3): 173-180, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29174090

RESUMO

Only a few subjects carrying supernumerary marker chromosomes derived from 19 chromosome (sSMC(19)) have been described to date and for a small portion of them the genic content has been defined at the molecular level. We present seven new different sSMCs(19) identified in eight individuals, seven of whom unrelated. The presence of the sSMC is associated with a clinical phenotype in five subjects, while the other three carriers, two of whom related, are normal. All sSMCs(19) have been characterized by means of conventional and molecular cytogenetics. We compare the sSMCs(19) carriers with a clinical phenotype to already described patients with gains (sSMCs or microduplications) of overlapping genomic regions with the aim to deepen the pathogenicity of the encountered imbalances and to assess the role of the involved genes on the phenotype. The present work supports the correlation between the gain of some chromosome 19 critical regions and specific phenotypes.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Aberrações Cromossômicas , Cromossomos Humanos Par 19 , Análise Citogenética/métodos , Estudos de Associação Genética , Adulto , Pré-Escolar , Feminino , Feto/metabolismo , Idade Gestacional , Humanos , Masculino , Mosaicismo
8.
Genet Med ; 19(6): 691-700, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27831545

RESUMO

PURPOSE: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined. METHODS: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations. RESULTS: Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis. CONCLUSION: This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.


Assuntos
Encéfalo/diagnóstico por imagem , Doença de Hirschsprung/diagnóstico por imagem , Deficiência Intelectual/diagnóstico por imagem , Imagem por Ressonância Magnética , Microcefalia/diagnóstico por imagem , Neuroimagem , Encéfalo/patologia , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/patologia , Facies , Feminino , Genótipo , Haploinsuficiência , Doença de Hirschsprung/genética , Doença de Hirschsprung/patologia , Humanos , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Estudos Longitudinais , Masculino , Microcefalia/genética , Microcefalia/patologia , Fenótipo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
9.
Nat Genet ; 48(7): 777-84, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27213289

RESUMO

We identified biallelic mutations in NANS, the gene encoding the synthase for N-acetylneuraminic acid (NeuNAc; sialic acid), in nine individuals with infantile-onset severe developmental delay and skeletal dysplasia. Patient body fluids showed an elevation in N-acetyl-D-mannosamine levels, and patient-derived fibroblasts had reduced NANS activity and were unable to incorporate sialic acid precursors into sialylated glycoproteins. Knockdown of nansa in zebrafish embryos resulted in abnormal skeletal development, and exogenously added sialic acid partially rescued the skeletal phenotype. Thus, NANS-mediated synthesis of sialic acid is required for early brain development and skeletal growth. Normal sialylation of plasma proteins was observed in spite of NANS deficiency. Exploration of endogenous synthesis, nutritional absorption, and rescue pathways for sialic acid in different tissues and developmental phases is warranted to design therapeutic strategies to counteract NANS deficiency and to shed light on sialic acid metabolism and its implications for human nutrition.


Assuntos
Doenças do Desenvolvimento Ósseo/patologia , Encéfalo/embriologia , Deficiências do Desenvolvimento/patologia , Mutação/genética , Oxo-Ácido-Liases/genética , Ácidos Siálicos/metabolismo , Peixe-Zebra/embriologia , Adulto , Idade de Início , Animais , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Pré-Escolar , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/metabolismo , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/patologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
10.
Clin Colorectal Cancer ; 15(3): e75-92, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26792031

RESUMO

BACKGROUND: Familial adenomatous polyposis (FAP) is one of the most important clinical forms of inherited susceptibility to colorectal cancer. So far, no accepted prognostic markers are present to monitor patients with FAP. Consequently, the major problem in managing patients with FAP is the difficulty to predict when the switch between adenoma and malignant carcinoma occurs, leading to the necessity of preventive surgery. Proteomics is one of the most suitable approaches to identify biomarkers, and it is widely used in cancer research. In this investigation, we studied the circulating plasma peptides in samples collected from patients with FAP and compared the obtained results with adenoma, colorectal cancer, and control samples to discover peptides able to distinguish different phenotypes. MATERIALS AND METHODS: The peptide fingerprint was obtained by matrix-assisted laser desorption/ionization coupled to time-of-flight mass spectrometry. After statistical analysis, a subset of 45 ionic species was found differently expressed in the 4 groups considered, 12 of them peculiar to patients with FAP. Moreover, 4 ionic species were found significantly changed in the switch between adenoma and malignant carcinoma. RESULTS: Potentially prognostic peptides identified by this study derive mainly from circulating proteins, some of which are involved in the inflammatory response, such as complement C3 and C4 subjected to an exoprotease activity that seemed pathology related. CONCLUSIONS: In this study, we defined for the first time a specific panel of peptides for monitoring patients with FAP that could be profitably used to monitor and predict the pathologic evolution in adenocarcinoma malignancy.


Assuntos
Polipose Adenomatosa do Colo/sangue , Biomarcadores Tumorais/sangue , Detecção Precoce de Câncer/métodos , Mapeamento de Peptídeos/métodos , Peptídeos/sangue , Polipose Adenomatosa do Colo/diagnóstico , Adulto , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteômica/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
11.
Am J Med Genet A ; 161A(2): 273-84, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23322667

RESUMO

Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and is characterized by distinctive facial features, epilepsy, moderate to severe intellectual disability, corpus callosum abnormalities and other congenital malformations. Epilepsy is considered a main manifestation of the syndrome, with a prevalence of about 70-75%. In order to delineate the electroclinical phenotype of epilepsy in MWS, we investigated epilepsy onset and evolution, including seizure types, EEG features, and response to anti-epileptic therapies in 22 patients with genetically confirmed MWS. Onset of seizures occurred at a median age of 14.5 months (range: 1-108 months). The main seizure types were focal and atypical absence seizures. In all patients the first seizure was a focal seizure, often precipitated by fever. The semiology was variable, including hypomotor, versive, or focal clonic manifestations; frequency ranged from daily to sporadic. Focal seizures were more frequent during drowsiness and sleep. In 13 patients, atypical absence seizures appeared later in the course of the disease, usually after the age of 4 years. Epilepsy was usually quite difficult to treat: seizure freedom was achieved in nine out of the 20 treated patients. At epilepsy onset, the EEGs were normal or showed only mild slowing of background activity. During follow-up, irregular, diffuse frontally dominant and occasionally asymmetric spike and waves discharges were seen in most patients. Sleep markedly activated these abnormalities, resulting in continuous or near-to-continuous spike and wave activity during slow wave sleep. Slowing of background activity and poverty of physiological sleep features were seen in most patients. Our data suggest that a distinct electroclinical phenotype, characterized by focal and atypical absence seizures, often preceded by febrile seizures, and age-dependent EEG changes, can be recognized in most patients with MWS.


Assuntos
Doença de Hirschsprung/fisiopatologia , Deficiência Intelectual/fisiopatologia , Microcefalia/fisiopatologia , Convulsões/fisiopatologia , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Análise Mutacional de DNA , Eletroencefalografia , Facies , Feminino , Doença de Hirschsprung/tratamento farmacológico , Doença de Hirschsprung/genética , Proteínas de Homeodomínio/genética , Humanos , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Masculino , Microcefalia/tratamento farmacológico , Microcefalia/genética , Mutação , Fenótipo , Proteínas Repressoras/genética , Estudos Retrospectivos , Convulsões/tratamento farmacológico , Convulsões/genética , Ácido Valproico/uso terapêutico , Adulto Jovem , Homeobox 2 de Ligação a E-box com Dedos de Zinco
12.
Surg Endosc ; 27(1): 207-13, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22773231

RESUMO

BACKGROUND: Currently, no guidelines exist for the treatment of patients with multiple colorectal adenomas (MCRAs) (>10 but <100 synchronous nondiminutive polyps of the large bowel). This retrospective study aimed to investigate the clinical and molecular factors related to different treatments for MCRAs. METHODS: Patients with MCRAs were consecutively enrolled from January 2003 to June 2011. Sequencing of their APC and MutYH genes was performed. The clinical, molecular, and family histories of the patients were collected using the Progeny database. The patient treatments were divided into three groups of increasing clinical weight: endoscopic polypectomy, segmental resection, and total colectomy. A logistic regression analysis of clinicomolecular factors related to different treatment options was performed. RESULTS: The study comprised 80 patients (32 women, 40%) with a median age of 53 years (range 13-74 years). The median number of polyps was 33 (range 10-90).The cases included 62 diffuse polyposis, 18 segmental polyposis coli and synchronous colorectal carcinomas (CRC; 34 cases, 43%). The pathogenetic mutations were biallelic MutYH (n = 19, 24%) and APC (n = 4, 5%). The mean follow-up period was 74 months (median 43 months, range 1-468 months). Endoscopic polypectomy was performed in 25 cases (31%), segmental resection in 16 cases (20%), and total colectomy in 39 cases (49%). The logistics regression analysis, considering all the patients, showed that the number of polyps, the presence of CRC, and mutation were correlated with more intensive treatment. For the patients without CRC, only the number of polyps was correlated with the severity of the treatment (p > 0.0166). "On the ROC (receiver operating characteristic) curve, 25 was the number of polyps that best discriminated between surgical and endoscopic therapy. CONCLUSIONS: The majority of patients with MCRAs undergo surgery. For patients without CRC, only the number of polyps, and not the presence of a disease-causing mutation, is correlated with increased heaviness of treatment. Patients with more than 25 polyps are more likely to undergo a surgical resection.


Assuntos
Pólipos Adenomatosos/cirurgia , Neoplasias do Colo/cirurgia , Colonoscopia/métodos , Proctoscopia/métodos , Neoplasias Retais/cirurgia , Pólipos Adenomatosos/genética , Adolescente , Adulto , Idoso , Neoplasias do Colo/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Curva ROC , Neoplasias Retais/genética , Estudos Retrospectivos , Adulto Jovem
13.
Int J Biol Markers ; 27(1): 13-9, 2012 Jan-Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22180177

RESUMO

PURPOSE: Germline nonsense and frameshift mutations in the adenomatous polyposis coli (APC) gene are found in approximately 90% of individuals affected by familial adenomatous polyposis (FAP) and a genotype-phenotype relationship has been observed. Missense mutations have also been found in a few cases, even if their role in FAP is still unknown. An association between a missense mutation, APC I1307K, and the risk of sporadic colorectal cancer (CRC) has been reported. In order to improve the knowledge about the genetic effect of APC I1307K on the phenotype, we tried a new approach using matrix-assisted laser desorption/ionization mass spectrometry (MALDI/MS). EXPERIMENTAL DESIGN: An APC mutation (I1307K) was found in an index case of a non-Jewish woman and her son with attenuated familial adenomatous polyposis (A-FAP) and no family history of cancer. In order to evaluate whether the presence and abundance of the ionic species are related to the presence of cancer or the presence of mutation, comparative analyses of 11 healthy clean-colon subjects, 59 patients with CRC (stage II n=19, stage III n=23, stage IV n=17) without polyps, and 9 FAP patients, carriers of a nonsense mutation in the APC gene, were evaluated. RESULTS: Comparative analysis of serum protein profiles of the index patient and her healthy son, FAP and sporadic CRC patients, and subjects with preneoplastic lesions showed a characteristic abundance of ionic species at m/z 905, which was not present in healthy controls. Two peptides were identified from MALDI/MS/MS spectra of m/z 905 belonging to the kininogen-1 precursor and the human forkhead box protein 01A (FOXO1A). FOXO1A was present in only two subjects carrying I1307K, but not in other patients. CONCLUSIONS: Our findings seem to suggest a relationship between m/z 905, FOXO1A and the development and growth of colorectal cancer. FOXO1A fragment determination in serum with MALDI/MS might be a promising approach for early detection of colon carcinoma or for the development of targeted therapies.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , Fatores de Transcrição Forkhead/genética , Genes APC , Adolescente , Adulto , Códon sem Sentido , Feminino , Proteína Forkhead Box O1 , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Análise de Sequência de DNA , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Adulto Jovem
14.
Genet Test Mol Biomarkers ; 14(5): 695-701, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20854099

RESUMO

The role of cryptic translocations in human syndromes is a matter of fact, though this phenomenon is apparently rare. Apart from episodic case reports due to the increasing application of new molecular cytogenetic techniques, no data on its frequency in the general population are currently available. Rearrangements due to the unbalanced segregation of cryptic translocations are found in many anomalies responsible for different clinical pictures. In nearly 50% of cases, subtelomeric abnormalities are inherited from a parent carrying a balanced cryptic chromosome rearrangement. To date, very few cases of partial trisomies of 19q have been reported, with different breakpoints. Involvement of the distal region 19q is even more rare, and the delineation of its main clinical characteristics is still vague and awaiting better definition. We report two new cases of partial 19q13.42-qter trisomy associated with a partial 20p13-pter monosomy in a family found to have the cryptic translocation t(19;20)(q13.42;p13). We investigated a 5-year-old boy and his 49-year-old paternal uncle, and both had a similar, previously unrecognized mental retardation pattern, associated with the same subtelomeric rearrangement.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 19/ultraestrutura , Cromossomos Humanos Par 20/ultraestrutura , Monossomia/genética , Translocação Genética/genética , Trissomia/genética , Anormalidades Múltiplas/genética , Pré-Escolar , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 20/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Linhagem
15.
Genet Med ; 12(7): 431-9, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20531206

RESUMO

PURPOSE: Nail-Patella syndrome (MIM 161200) is a rare autosomal dominant disorder characterized by hypoplastic or absent patellae, dystrophic nails, dysplasia of the elbows, and iliac horn. In 40% of cases, a glomerular defect is present and, less frequently, ocular damage is observed. Inter- and intrafamilial variable expressivity of the clinical phenotype is a common finding. Mutations in the human LMX1B gene have been demonstrated to be responsible for Nail-Patella syndrome in around 80% of cases. METHODS: Standard polymerase chain reaction and sequencing methods were used for mutation and single nucleotide polymorphism identification and control of cloned sequences. Array-CGH (Agilent, 244A Kit) was used for detection of deletions. Standard cloning techniques and the Snapshot method were used for analysis of mosaicism. RESULTS: In this study, we present the results of LMX1B screening of 20 Nail-Patella syndrome patients. The molecular defect was found in 17 patients. We report five novel mutations and a approximately 2 Mb deletion in chromosome 9q encompassing the entire LMX1B gene in a patient with a complex phenotype. We present evidence of somatic mosaicism in unaffected parents in two cases, which, to our knowledge, are the first reported cases of inheritance of a mutated LMX1B allele in Nail-Patella syndrome patients from a mosaic parent. CONCLUSION: The study of the described case series provides some original observations in an "old" genetic disorder.


Assuntos
Deleção Cromossômica , Proteínas de Homeodomínio/genética , Mosaicismo , Síndrome da Unha-Patela/genética , Mutação Puntual/genética , Fatores de Transcrição/genética , Criança , Cromossomos Humanos Par 9/genética , Hibridização Genômica Comparativa , Feminino , Humanos , Proteínas com Homeodomínio LIM , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Pais , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Prognóstico
16.
Surg Neurol ; 71(2): 167-71, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18207546

RESUMO

BACKGROUND: Cerebral cavernous malformations are vascular malformations that affect the CNS and have been associated with cutaneous, retinal, and hepatic lesions. Until now, vertebral hemangiomas associated with CCM have been described only in one case. The coexistence of intracranial and spinal cavernous angiomas in familial CCM is extremely rare. In addition to previous studies, the occurrence of spinal, vertebral, and cutaneous cavernous angiomas is now described in different members of a large family with CCM. CASE DESCRIPTION: Our study reports a previously described family (IFCAS-07) with 12 members affected by autosomal dominant cavernous angiomas: 11 had CCM either alone or associated with hepatic or retinal angiomas, and one had only hepatic angioma. In all 11 members affected by CCM, the mutation of CCM1 gene was detected. During the follow-up, 8 subjects underwent a spinal MRI: 2 because they were symptomatic (thoracic paresthesias, enuresis, back pain) and 6 as a screening examination. Spinal MRI showed in 5 subjects spinal cavernous angiomas either alone or associated with vertebral hemangiomas. CONCLUSIONS: To our knowledge, this is the largest family reported with different subjects affected by CCM associated with multiple cavernous angiomas throughout (brain and spinal cord) and besides (retina, skin, liver, and vertebral column) the CNS. Comprehensive care of patients with familial CCM includes screening of all the tissues that can be affected and appropriate management by specialists. We emphasize the importance of spinal MRI in the diagnosis of spinal and vertebral cavernous angiomas in all patients affected by familial CCM.


Assuntos
Neoplasias do Sistema Nervoso Central/etiologia , Malformações Vasculares do Sistema Nervoso Central/complicações , Hemangioma Cavernoso/etiologia , Neoplasias da Coluna Vertebral/etiologia , Adulto , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/terapia , Malformações Vasculares do Sistema Nervoso Central/genética , Estudos de Coortes , Feminino , Hemangioma Cavernoso/diagnóstico , Hemangioma Cavernoso/terapia , Humanos , Proteína KRIT1 , Masculino , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Linhagem , Proteínas Proto-Oncogênicas/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/terapia , Neoplasias da Coluna Vertebral/diagnóstico , Neoplasias da Coluna Vertebral/terapia , Adulto Jovem
17.
Cancer Lett ; 268(2): 308-13, 2008 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-18495334

RESUMO

Biallelic germline mutations in the MYH gene cause MYH-Associated Polyposis but patients with a single mutation possibly have an increased colorectal cancer (CRC) risk. Using DNA from consecutive CRC patients we carried out a case-control study, with the aim to contribute data on the Italian population. Genotyping of four MYH mutations found two biallelic and two monoallelic carriers among 439 cases, and only one heterozygous individual among 247 age-matched controls. The frequencies of the mutant alleles were 0.68% (6/878) and 0.20% (1/494), respectively. These differences were not statistically significant. Results on the monoallelic carriers were combined with those from 11 studies on other populations, and the risk of developing a CRC was estimated with an OR=1.11 (95% CI=0.90; 1.36), yet not reaching a significant evidence of increased CRC risk.


Assuntos
Neoplasias Colorretais/genética , DNA Glicosilases/genética , Predisposição Genética para Doença , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
18.
Am J Med Genet A ; 121A(3): 214-8, 2003 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-12923860

RESUMO

Congenital malformations (CM) affect 2-3% of all births, the cause of which, when known, is genetic in 80-90% of cases. A genetic consultation (GC) is indicated for the parents of a child affected by a CM. This study analyzes the parental utilization of genetic counseling (GCU) and its possible influencing factors after termination of pregnancy (TOP) because of fetal anomalies or after the birth of a child affected by a major malformation. The study concerns cases in North-East Italy where there is a CM registry and a center-satellite system for genetic counseling. The results of this analysis are also compared to other similar studies, which address the same topic. Between 1981 and 2000, 1,235 out of 14,888 GC were performed because of the presence of a CM in a child/fetus. In the same period, 4,933 births and 1,112 TOPs were registered. The overall GCU was 19%, with significant differences according to malformative phenotype, severity of the malformative condition, type of birth, and viability. Genetic counseling was performed significantly sooner following TOP than after the birth of a malformed child. GCU showed an unequal distribution according to the parents' place of residence, suggesting that easy and equal access to the genetic service was probably not well provided for. Our results suggest that genetic services should be integrated with related services, and that the public and physicians need a greater awareness of these services.


Assuntos
Anormalidades Congênitas , Aconselhamento Genético/estatística & dados numéricos , Pais/psicologia , Pré-Escolar , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/genética , Feminino , Morte Fetal , Humanos , Lactente , Recém-Nascido , Itália/epidemiologia , Países Baixos/epidemiologia , Cooperação do Paciente , Gravidez , Resultado da Gravidez/epidemiologia , Diagnóstico Pré-Natal
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