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1.
Arch Esp Urol ; 72(10): 1038-1042, 2019 Dec.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31823853

RESUMO

OBJECTIVES: To evaluate the impact of common Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutations, 5T polymorphism and presence of severe Cystic Fibrosis (CF) on fertility outcomes with Assisted Reproductive Techniques (ART) in patients presenting Congenital Bilateral Absence of Vas Deferens (CBAVD). METHODS: A comparative observational cohort study was performed from 2002 to 2018 with 51 patients with diagnosis of CBAVD. Presence of CFTR mutations and 5T, CF, pregnancy and newborn rates were analyzed. RESULTS: 80.4% percent had some mutation of CFTR gene being ΔF508 the most common (51%). The most frequently described genotype was the 7T/9T (31.4%) with the presence of 5T polymorphism in up to 25.5% of cases. Global newborn rates were 34% in the group using partner spermatozoa. When comparing 5T presence, we observed a decrease in newborn rates when carrying this mutation, without obtaining statistical significance (newborn rate: 5T/non-5T: 7.1/28%, p 0.45). No differences were found when comparing presence of severe CF, common CFTR gene mutations and ICSI-related parameters. CONCLUSION: The analysis of the presence of 5T polymporphism in CBAVD patients may add information when predicting the outcome of assisted reproductive techniques.


Assuntos
Doenças Urogenitais Masculinas , Técnicas de Reprodução Assistida , Ducto Deferente/anormalidades , Estudos de Coortes , Regulador de Condutância Transmembrana em Fibrose Cística , Feminino , Humanos , Recém-Nascido , Masculino , Doenças Urogenitais Masculinas/genética , Gravidez
2.
Artigo em Inglês | MEDLINE | ID: mdl-30675318

RESUMO

Background: Approximately 5 to 10% of all cancers are caused by inherited germline mutations, many of which are associated with different Hereditary Cancer Syndromes (HCS). In the context of the Program of Hereditary Cancer of the Valencia Community, individuals belonging to specific HCS and their families receive genetic counselling and genetic testing according to internationally established guidelines. The current diagnostic approach is based on sequencing a few high-risk genes related to each HCS; however, this method is time-consuming, expensive and does not achieve a confirmatory genetic diagnosis in many cases. This study aims to test the level of improvement offered by a Next Generation Sequencing (NGS) gene-panel compared to the standard approach in a diagnostic reference laboratory setting. Methods: A multi-gene NGS panel was used to test a total of 91 probands, previously classified as non-informative by analysing the high-risk genes defined in our guidelines. Results: Nineteen deleterious mutations were detected in 16% of patients, some mutations were found in already-tested high-risk genes (BRCA1, BRCA2, MSH2) and others in non-prevalent genes (RAD51D, PALB2, ATM, TP53, MUTYH, BRIP1). Conclusions: Overall, our findings reclassify several index cases into different HCS, and change the mutational status of 14 cases from non-informative to gene mutation carriers. In conclusion, we highlight the necessity of incorporating validated multi-gene NGS panels into the HCSs diagnostic routine to increase the performance of genetic diagnosis.

3.
Int J Genomics ; 2017: 4798474, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28630856

RESUMO

We report on three nonrelated patients with intellectual disability and CNVs that give rise to three new chimeric genes. All the genes forming these fusion transcripts may have an important role in central nervous system development and/or in gene expression regulation, and therefore not only their deletion or duplication but also the resulting chimeric gene may contribute to the phenotype of the patients. Deletions and duplications are usually pathogenic when affecting dose-sensitive genes. Alternatively, a chimeric gene may also be pathogenic by different gain-of-function mechanisms that are not restricted to dose-sensitive genes: the emergence of a new polypeptide that combines functional domains from two different genes, the deregulated expression of any coding sequence by the promoter region of a neighboring gene, and/or a putative dominant-negative effect due to the preservation of functional domains of partially truncated proteins. Fusion oncogenes are well known, but in other pathologies, the search for chimeric genes is disregarded. According to our findings, we hypothesize that the frequency of fusion transcripts may be much higher than suspected, and it should be taken into account in the array-CGH analyses of patients with intellectual disability.

4.
J Med Genet ; 54(2): 87-92, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27620904

RESUMO

BACKGROUND: Intellectual disability is a very complex condition where more than 600 genes have been reported. Due to this extraordinary heterogeneity, a large proportion of patients remain without a specific diagnosis and genetic counselling. The need for new methodological strategies in order to detect a greater number of mutations in multiple genes is therefore crucial. METHODS: In this work, we screened a large panel of 1256 genes (646 pathogenic, 610 candidate) by next-generation sequencing to determine the molecular aetiology of syndromic intellectual disability. A total of 92 patients, negative for previous genetic analyses, were studied together with their parents. Clinically relevant variants were validated by conventional sequencing. RESULTS: A definitive diagnosis was achieved in 29 families by testing the 646 known pathogenic genes. Mutations were found in 25 different genes, where only the genes KMT2D, KMT2A and MED13L were found mutated in more than one patient. A preponderance of de novo mutations was noted even among the X linked conditions. Additionally, seven de novo probably pathogenic mutations were found in the candidate genes AGO1, JARID2, SIN3B, FBXO11, MAP3K7, HDAC2 and SMARCC2. Altogether, this means a diagnostic yield of 39% of the cases (95% CI 30% to 49%). CONCLUSIONS: The developed panel proved to be efficient and suitable for the genetic diagnosis of syndromic intellectual disability in a clinical setting. Next-generation sequencing has the potential for high-throughput identification of genetic variations, although the challenges of an adequate clinical interpretation of these variants and the knowledge on further unknown genes causing intellectual disability remain to be solved.


Assuntos
Exoma/genética , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Deficiência Intelectual/genética , Feminino , Humanos , Deficiência Intelectual/patologia , Masculino , Mutação
5.
Leuk Lymphoma ; 58(7): 1686-1693, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27771989

RESUMO

The incidence of SF3B1 mutations in patients with RARS is high. Recently, it has been shown that SF3B1 and DNMT3A mutations overlap more often than expected, although it is not clear how this could affect the disease. We studied SF3B1 and DNMT3A in 123 RARS patients: 101 out of 123 samples (82%) had somatic mutations in SF3B1, and 13 of them (13%) showed a co-mutation (SF3B1mutDNMT3Amut). All co-mutated patients had a normal karyotype, and 12 of them (92%) were lower-risk patients (IPSS and IPSS-R). Despite their favorable profile, SF3B1mutDNMT3Amut patients showed a higher RBC transfusion dependency (92% versus 48%, p = .007), a shorter overall survival (OS) (median, 30 versus 97 months, p = .034), and a higher risk of progression to acute myeloid leukemia (AML) at 5 years (25% versus 2%, p = .023) than SF3B1mutDNMT3Awt patients. In conclusion, DNMT3A mutations are present in a significant proportion of SF3B1mut patients with a negative clinical impact.


Assuntos
Anemia Refratária/genética , Anemia Refratária/mortalidade , Anemia Sideroblástica/genética , Anemia Sideroblástica/mortalidade , DNA (Citosina-5-)-Metiltransferases/genética , Mutação , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Refratária/diagnóstico , Anemia Sideroblástica/diagnóstico , Aberrações Cromossômicas , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico
6.
Pediatr Res ; 80(6): 809-815, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27500536

RESUMO

BACKGROUND: Mutations in the X-linked gene MED12 cause at least three different, but closely related, entities of syndromic intellectual disability. Recently, a new syndrome caused by MED13L deleterious variants has been described, which shows similar clinical manifestations including intellectual disability, hypotonia, and other congenital anomalies. METHODS: Genotyping of 1,256 genes related with neurodevelopment was performed by next-generation sequencing in three unrelated patients and their healthy parents. Clinically relevant findings were confirmed by conventional sequencing. RESULTS: Each patient showed one de novo variant not previously reported in the literature or databases. Two different missense variants were found in the MED12 or MED13L genes and one nonsense mutation was found in the MED13L gene. CONCLUSION: The phenotypic consequences of these mutations are closely related and/or have been previously reported in one or other gene. Additionally, MED12 and MED13L code for two closely related partners of the mediator kinase module. Consequently, we propose the concept of a common MED12/MED13L clinical spectrum, encompassing Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, Ohdo syndrome, MED13L haploinsufficiency syndrome, and others.


Assuntos
Deficiência Intelectual/genética , Complexo Mediador/genética , Mutação , Anormalidades Múltiplas/genética , Substituição de Aminoácidos , Criança , Códon sem Sentido , Análise Mutacional de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Proteínas Mutantes/genética , Mutação de Sentido Incorreto , Fenótipo , Síndrome , Adulto Jovem
7.
J Cancer Res Clin Oncol ; 142(3): 573-80, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26498952

RESUMO

PURPOSE: In metastatic neuroblastoma (NB) patients, accurate risk stratification and disease monitoring would reduce relapse probabilities. This study aims to evaluate the independent prognostic significance of detecting tyrosine hydroxylase (TH) and doublecortin (DCX) mRNAs by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in peripheral blood (PB) and bone marrow (BM) samples from metastatic NB patients. PROCEDURES: RT-qPCR was performed on PB and BM samples from metastatic NB patients at diagnosis, post-induction therapy and at the end of treatment for TH and DCX mRNAs detection. RESULTS: High levels of TH and DCX mRNAs when detected in PB and BM at diagnosis independently predicted worse outcome in a cohort of 162 metastatic NB. In the subgroup of high-risk metastatic NB, TH mRNA detected in PB remained as independent predictor of EFS and OS at diagnosis. After the induction therapy, high levels of TH mRNA in PB and DCX mRNA in BM independently predicted poor EFS and OS. Furthermore TH mRNA when detected in BM predicted worse EFS. TH mRNA in PB samples at the end of treatment is an independent predictor of worse outcome. CONCLUSION: TH and DCX mRNAs levels in PB and BM assessed by RT-qPCR should be considered in new pre-treatment risk stratification strategies to reliable estimate outcome differences in metastatic NB patients. In those high-risk metastatic NB, TH and DCX mRNA quantification could be used for the assessment of response to treatment and for early detection of progressive disease or relapses.


Assuntos
Medula Óssea/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Neuroblastoma/genética , Neuroblastoma/patologia , Neuropeptídeos/genética , Tirosina 3-Mono-Oxigenase/genética , Adolescente , Adulto , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Medula Óssea/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas Associadas aos Microtúbulos/sangue , Metástase Neoplásica , Neuroblastoma/sangue , Neuropeptídeos/sangue , Prognóstico , RNA Mensageiro/sangue , RNA Mensageiro/metabolismo , Tirosina 3-Mono-Oxigenase/sangue , Adulto Jovem
8.
Am J Hum Genet ; 97(6): 922-32, 2015 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-26637982

RESUMO

We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome.


Assuntos
Deficiências do Desenvolvimento/genética , Histona Acetiltransferases/genética , Deficiência Intelectual/genética , Doenças Neurodegenerativas/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Adolescente , Animais , Criança , Pré-Escolar , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Modelos Animais de Doenças , Elementos E-Box , Facies , Família , Regulação da Expressão Gênica , Histona Acetiltransferases/metabolismo , Humanos , Lactente , Padrões de Herança , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Mutação , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Linhagem , Fenótipo , Transdução de Sinais , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Fator de Transcrição TFIID/metabolismo , Adulto Jovem , Peixe-Zebra
10.
Pediatr Res ; 78(5): 533-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26200704

RESUMO

BACKGROUND: Only 15 point mutations in NFIX gene have been reported so far, nine of them cause the Marshall-Smith syndrome (MSS) and the remaining mutations lead to an overgrowth disorder with a less severe phenotype, defined as Sotos-like. METHODS: The clinical findings in three patients with MSS and two patients with a Sotos-like phenotype are presented. Analysis of the NFIX gene was performed both by conventional or next-generation sequencing. RESULTS: Five de novo mutations in NFIX gene were identified, four of them not previously reported. Two frameshift mutations and a donor-splice one caused MSS, while two missense mutations in the DNA binding/dimerisation domain entailed an overgrowth syndrome with some clinical features resembling Sotos syndrome, accompanied by a marfanoid habitus, very low BMI, long narrow face, or arachnodactyly. CONCLUSION: Marshall-Smith mutations are scattered through exons 6-10 of NFIX gene, while most point mutations causing an overgrowth syndrome are clustered in exon 2. Clinical features of this overgrowth syndrome may well be considered an intermediate phenotype between Sotos and Marfan syndromes.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Mutação , Fatores de Transcrição NFI/genética , Displasia Septo-Óptica/genética , Síndrome de Sotos/genética , Anormalidades Múltiplas/diagnóstico , Sequência de Aminoácidos , Sequência de Bases , Doenças do Desenvolvimento Ósseo/diagnóstico , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Análise Mutacional de DNA/métodos , Éxons , Evolução Fatal , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Fenótipo , Displasia Septo-Óptica/diagnóstico , Síndrome de Sotos/diagnóstico , Adulto Jovem
11.
Biomed Res Int ; 2015: 341986, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26106604

RESUMO

Alterations of epigenetic mechanisms, and more specifically imprinting modifications, could be responsible of neurodevelopmental disorders such as intellectual disability (ID) or autism together with other associated clinical features in many cases. Currently only eight imprinting syndromes are defined in spite of the fact that more than 200 genes are known or predicted to be imprinted. Recent publications point out that some epimutations which cause imprinting disorders may affect simultaneously different imprinted loci, suggesting that DNA-methylation may have been altered more globally. Therefore, we hypothesised that the detection of altered methylation patterns in known imprinting loci will indirectly allow identifying new syndromes due to epimutations among patients with unexplained ID. In a screening for imprinting alterations in 412 patients with syndromic ID/autism we found five patients with altered methylation in the four genes studied: MEG3, H19, KCNQ1OT1, and SNRPN. Remarkably, the cases with partial loss of methylation in KCNQ1OT1 and SNRPN present clinical features different to those associated with the corresponding imprinting syndromes, suggesting a multilocus methylation defect in accordance with our initial hypothesis. Consequently, our results are a proof of concept that the identification of epimutations in known loci in patients with clinical features different from those associated with known syndromes will eventually lead to the definition of new imprinting disorders.


Assuntos
Impressão Genômica , Transtornos do Neurodesenvolvimento/genética , Proteínas Centrais de snRNP/genética , Adulto , Criança , Pré-Escolar , Metilação de DNA/genética , Epigênese Genética , Feminino , Dosagem de Genes/genética , Humanos , Masculino , Mutação , Transtornos do Neurodesenvolvimento/patologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética
12.
Rev. neurol. (Ed. impr.) ; 60(9): 408-412, 1 mayo, 2015. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-138044

RESUMO

Introducción. El síndrome de Noonan (SN) y otros síndromes con fenotipo similar, como LEOPARD, cardiofaciocutáneo, Costello y Legius, están asociados a mutaciones en genes incluidos en la vía RAS/MAPK (rasopatías), una importante vía de señalización relacionada con la proliferación celular. El descenso de las amígdalas cerebelares dentro del canal medular cervical, conocido como malformación de Arnold-Chiari (MAC), se ha descrito en pacientes afectos de SN, lo que ha llevado a sugerir que la MAC podría formar parte del espectro fenotípico del SN. Presentamos dos casos con SN y MAC. Casos clínicos. Caso 1: mujer de 29 años con fenotipo de Noonan. Fue intervenida a los 9 años de estenosis valvular pulmonar. A los 27 años, presentó MAC sintomática que precisó descompresión quirúrgica. Presentaba mutación c.922A>G (N308D) en el gen PTPN perteneciente a la vía RAS/MAPK. Caso 2: niña de 10 años con fenotipo de Noonan y MAC asintomática detectada en resonancia magnética cerebral. Era portadora de la mutación c.923A>G (N308S) en el gen PTPN11. Conclusiones. Hemos encontrado en la bibliografía seis pacientes con esta asociación, cuatro con fenotipo Noonan y dos con LEOPARD. Nuestros dos pacientes aportan evidencia suplementaria a la hipótesis de que la MAC formaría parte del espectro fenotípico del SN. El escaso número de pacientes publicados con esta asociación no permite extraer recomendaciones sobre el momento y la frecuencia de estudio de neuroimagen; no obstante, una exploración neurológica cuidadosa debería incluirse en la guía anticipatoria de salud en los síndromes de la vía RAS/MAPK (AU)


Introduction. Noonan syndrome (NS) and other syndromes with a similar phenotype, such as LEOPARD, cardiofaciocutaneous, Costello and Legius, are associated to mutations in genes included in the RAS/MAPK pathway (RASopathies), which is an important signalling pathway related to cell proliferation. Tonsillar descent into the upper cervical spinal canal, known as Arnold-Chiari malformation (ACM), has been reported in patients with NS and this has led some researchers to suggest that ACM could be part of the phenotypic spectrum of NS. We report two cases of NS and ACM. Case reports. Case 1: 29-year-old female with Noonan phenotype who underwent surgery at the age of nine years due to pulmonary valve stenosis. At the age of 27, she presented symptomatic ACM that required surgical decompression. She presented the c.922A>G (N308D) mutation in the gene PTPN that belongs to the RAS/MAPK pathway. Case 2: a 10-yearold female with Noonan phenotype and asymptomatic ACM detected in magnetic resonance imaging of the brain. She was a carrier of the c.923A>G (N308S) mutation in gene PTPN11. Conclusions. Six patients with this association have been found in the literature, four with the Noonan phenotype and two with LEOPARD. Our two patients provide supplementary evidence that backs up the hypothesis by which ACM would be part of the phenotypic spectrum of NS. The small number of reported cases of patients with this association does not allow us to draw up recommendations about when and how often neuroimaging studies should be performed; a careful neurological examination, however, should be included in the anticipatory health guidelines in syndromes involving the RAS/MAPK pathway (AU)


Assuntos
Adulto , Criança , Feminino , Humanos , Malformação de Arnold-Chiari/epidemiologia , Síndrome de Noonan/complicações , Síndrome LEOPARD/complicações , Anormalidades Craniofaciais/complicações , Neuroimagem
13.
Am J Med Genet A ; 167(7): 1614-20, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25858326

RESUMO

This paper describes the presence of an interstitial pure duplication of 19p13.3 (4.95 Mb) in a patient with intellectual disability studied by array-CGH which was initially considered as a de novo alteration. The discovery of the same chromosomal alteration in a first-degree cousin of this patient led us to investigate the presence of insertional translocations, which were consequently found in three family generations. The same duplication was found in three intellectually disabled patients and among the translocation carrier family members a very high incidence of miscarriages are reported. A review of other published cases has allowed us to find three other patients with a similar pure duplication, all of them sharing some common clinical findings such as intrauterine growth retardation, microcephaly, motor and speech delay, moderate to severe intellectual disability, and dysmorphic features. These findings allow us to suggest the presence of a new microduplication syndrome in chromosomal region 19p13.3.


Assuntos
Anormalidades Múltiplas/genética , Transtornos Cromossômicos/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 19/genética , Deficiência Intelectual/genética , Microcefalia/genética , Hibridização Genômica Comparativa , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Síndrome
14.
Rev Neurol ; 60(9): 408-12, 2015 May 01.
Artigo em Espanhol | MEDLINE | ID: mdl-25912702

RESUMO

INTRODUCTION: Noonan syndrome (NS) and other syndromes with a similar phenotype, such as LEOPARD, cardiofaciocutaneous, Costello and Legius, are associated to mutations in genes included in the RAS/MAPK pathway (RASopathies), which is an important signalling pathway related to cell proliferation. Tonsillar descent into the upper cervical spinal canal, known as Arnold-Chiari malformation (ACM), has been reported in patients with NS and this has led some researchers to suggest that ACM could be part of the phenotypic spectrum of NS. We report two cases of NS and ACM. CASE REPORTS: Case 1: 29-year-old female with Noonan phenotype who underwent surgery at the age of nine years due to pulmonary valve stenosis. At the age of 27, she presented symptomatic ACM that required surgical decompression. She presented the c.922A>G (N308D) mutation in the gene PTPN that belongs to the RAS/MAPK pathway. Case 2: a 10-year-old female with Noonan phenotype and asymptomatic ACM detected in magnetic resonance imaging of the brain. She was a carrier of the c.923A>G (N308S) mutation in gene PTPN11. CONCLUSIONS: Six patients with this association have been found in the literature, four with the Noonan phenotype and two with LEOPARD. Our two patients provide supplementary evidence that backs up the hypothesis by which ACM would be part of the phenotypic spectrum of NS. The small number of reported cases of patients with this association does not allow us to draw up recommendations about when and how often neuroimaging studies should be performed; a careful neurological examination, however, should be included in the anticipatory health guidelines in syndromes involving the RAS/MAPK pathway.


Assuntos
Malformação de Arnold-Chiari/etiologia , Síndrome de Noonan/complicações , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Transdução de Sinais/fisiologia , Adulto , Malformação de Arnold-Chiari/cirurgia , Criança , Descompressão Cirúrgica , Éxons , Feminino , Humanos , Síndrome LEOPARD/complicações , Síndrome LEOPARD/genética , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Mutação de Sentido Incorreto , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Síndrome de Noonan/metabolismo , Fenótipo , Mutação Puntual , Gravidez , Complicações na Gravidez/genética , Diagnóstico Pré-Natal , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/genética
15.
Am J Med Genet A ; 167(6): 1342-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25900314

RESUMO

The NSDHL gene encodes 3ß-hydroxysteroid dehydrogenase involved in one of the later steps of the cholesterol biosynthetic pathway. Mutations in this gene can cause CHILD syndrome (OMIM 308050) and CK syndrome (OMIM 300831). CHILD syndrome is an X-linked dominant, male lethal disorder caused by mutations in the NSDHL gene that result in the loss of the function of the NSDHL protein. CK syndrome is an allelic X-linked recessive disorder. So far, 13 patients with CK syndrome from two families have been reported on. We present a new five-generation family with affected males manifesting clinical features of CK syndrome. Next generation sequencing was targeted to a custom panel of 542 genes with known or putative implication on intellectual disability. Missense mutation p.Gly152Asp was identified in the NSDHL gene in the DNA sample of the affected male. Mutation carrier status was confirmed for all the obligate carriers in the family. The clinical features of the affected males in the family manifested as weak fetal movements, severe intellectual disability, seizures, spasticity, atrophy of optic discs, microcephaly, plagiocephaly, skeletal abnormalities, and minor facial anomalies, including a high nasal bridge, strabismus, and micrognathia. A highly significant preferential transmission of the mutation was observed in this and previous families segregating CK syndrome. Our report expands the clinical spectrum of this syndrome to include weak fetal movements, spasticity, and plagiocephaly, and transmission ratio distortion. The various findings in these patients increase our understanding of the diversity of the clinical presentation of cholesterol biosynthesis disorders.


Assuntos
3-Hidroxiesteroide Desidrogenases/genética , Anormalidades Múltiplas/genética , Epilepsia Tônico-Clônica/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Eritrodermia Ictiosiforme Congênita/genética , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/genética , Mutação de Sentido Incorreto , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Alelos , Epilepsia Tônico-Clônica/diagnóstico , Epilepsia Tônico-Clônica/patologia , Feminino , Expressão Gênica , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Eritrodermia Ictiosiforme Congênita/diagnóstico , Eritrodermia Ictiosiforme Congênita/patologia , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/patologia , Lituânia , Masculino , Linhagem
16.
Eur J Cancer ; 50(13): 2241-50, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24953332

RESUMO

BACKGROUND AND AIMS: Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having 'Lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposis patients show some phenotypic similarities to Lynch syndrome patients. The aim of this study was to investigate the prevalence of germline MUTYH mutations in a large series of LLS patients. METHODS: Two hundred and twenty-five probands fulfilling LLS criteria were included in this study. Screening of MUTYH recurrent mutations, whole coding sequencing and a large rearrangement analysis were undertaken. Age, sex, clinical, pathological and molecular characteristics of tumours including KRAS mutations were assessed. RESULTS: We found a prevalence of 3.1% of MAP syndrome in the whole series of LLS (7/225) and 3.9% when only cases fulfilling clinical criteria were considered (7/178). Patients with MUTYH biallelic mutations had more adenomas than monoallelic (P=0.02) and wildtype patients (P<0.0001). Six out of nine analysed tumours from six biallelic MUTYH carriers harboured KRAS-p.G12C mutation. This mutation was found to be associated with biallelic MUTYH germline mutation when compared with reported series of unselected colorectal cancer cohorts (P<0.0001). CONCLUSIONS: A proportion of unexplained LLS cases is caused by biallelic MUTYH mutations. The obtained results further justify the inclusion of MUTYH in the diagnostic strategy for Lynch syndrome-suspected patients.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , DNA Glicosilases/genética , Mutação em Linhagem Germinativa , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genética
17.
Med. clín (Ed. impr.) ; 142(12): 531-537, jun. 2014. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-122582

RESUMO

Fundamento y objetivo: Las alteraciones genómicas desequilibradas (duplicaciones o deleciones) causantes de trastornos del neurodesarrollo (TND) son en su mayoría episodios de novo. Sin embargo, también pueden surgir como consecuencia de reordenamientos equilibrados no detectados en uno de los progenitores, cambiando radicalmente el riesgo de recurrencia y el consejo genético de estos casos. La técnica de fluorescence in situ hybridization (FISH, «hibridación in situ fluorescente») permite la identificación y localización de reordenamientos cromosómicos tanto equilibrados como desequilibrados, identificando la ubicación de los segmentos duplicados. En este trabajo se pretende localizar en el genoma los segmentos duplicados detectados en pacientes con TND, e identificar aquellos casos debidos a reordenamientos heredados. Pacientes y método: El estudio se llevó a cabo en 13 pacientes con TND y portadores de duplicaciones génicas detectadas por compared genomic hybridization-array (CGH-array, «hibridación genómica comparada sobre arrays»). Se utilizaron 2 aproximaciones de la técnica FISH: hibridación con sondas de pintado cromosómico y con sondas específicas de cada duplicación. Resultados: En la serie de 13 pacientes con duplicación estudiados, se han encontrado 11 con duplicaciones en tándem, un caso con una traslocación insercional intracromosómica, y otro con una traslocación insercional intercromosómica. Por tanto, 2 de las duplicaciones que se habían considerado de novo habían sido, en realidad, heredadas de forma desequilibrada de un progenitor que era portador equilibrado del reordenamiento. Conclusión: Los resultados ponen de manifiesto la necesidad de caracterizar, mediante la técnica de FISH, los reordenamientos que se detectan por CGH-array, para identificar los casos con un elevado riesgo de recurrencia y realizar un correcto asesoramiento genético (AU)


Background and objective: An important proportion of neurodevelopmental disorders (NDDs) results from unbalanced genomic alterations (duplication or deletion). These chromosomal rearrangements may be considered as de novo, despite they arise as a result of a balanced rearrangement not detected in a phenotypically normal parent. Therefore, if the rearrangements are inherited, the recurrence risk and the genetic counseling of these cases change radically. Fluorescence in situ hybridization (FISH) is a technique that allows detecting both balanced and unbalanced rearrangements, identifying also the location of duplicated segments. We tried to locate in the genome the duplicated segments detected in patients with NDDs in order to identify those cases due to inherited rearrangements. Patients and method: The study was conducted in 13 patients with NDDs and genomic duplications detected by compared genomic hybridization-array (CGH-array). Two approaches of FISH technique were taken: hybridization with painting chromosome probes and with specific probes for each duplication. Results: In the studied series of 13 patients with duplication, 11 patients were found to carry tandemduplications, one with an intrachromosomal insertional translocation, and another with an interchromosomal insertional translocation. Therefore, 2 of the duplications considered de novo were actually an unbalanced rearrangement inherited from a parent who is a balanced carrier. Conclusion: The results illustrate the need to characterize by FISH technique the rearrangements that are detected by CGH-array to identify those cases with a high risk of recurrence (AU)


Assuntos
Humanos , Masculino , Feminino , Duplicação Cromossômica/genética , Duplicações Segmentares Genômicas/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Hibridização in Situ Fluorescente/métodos , Hibridização Genômica Comparativa/métodos , Mutagênese Insercional/métodos , Predisposição Genética para Doença/genética , Marcadores Genéticos/genética , Desequilíbrio Alélico/genética
18.
Eur J Paediatr Neurol ; 18(5): 558-66, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24815074

RESUMO

BACKGROUND: Nowadays the microarray technology allows whole-genome analysis with a high resolution and performance for the genetic diagnosis in any patient with intellectual disability or autism spectrum disorder. However in the immediate future, with the development of massive sequencing systems for application at clinical diagnosis, it will be necessary to have clinical criteria to guide studies. AIM: To perform an exhaustive clinical definition of patients with pathogenic copy number variations in order to establish the clinical criteria most suggestive of this kind of genomic rearrangements. METHOD: We designed and implemented a database to collect 190 different clinical variables (pregnancy, neonatal, facial dysmorphism, congenital anomalies, neurological features and family history) in a series of 246 patients, with developmental delay/intellectual disability. All cases were studied with array comparative genomic hybridization. RESULTS: We have found a pathogenic genomic imbalance in 73 patients. Frequency analysis of all clinical variables showed that growth disorder, abnormalities of hands, low-set ears and hypertelorism are the more frequent features among patients with genomic rearrangements. However other clinical features, such as genital abnormalities and aggressiveness, are more specifically associated with pathogenic copy number variations in spite of their low frequencies in the overall series, yielding higher statistical significance values than other traits. CONCLUSIONS: The genotype-phenotype comparison may be useful to set in the future the main clinical manifestations associated with deletions, duplications and unbalanced translocations. Theses analyses will improve the clinical indications and protocols to implement genomic arrays in the genetic study of patients with neurodevelopment disorders.


Assuntos
Aberrações Cromossômicas , Variações do Número de Cópias de DNA/genética , Genoma/genética , Deficiência Intelectual/genética , Fenótipo , Criança , Bases de Dados Genéticas , Deficiências do Desenvolvimento/diagnóstico , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/etiologia , Masculino , Análise em Microsséries
19.
Am J Med Genet A ; 164A(4): 918-23, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24458433

RESUMO

Here we report on two unrelated male patients with syndromic intellectual disability (ID) due to duplication at Xq13.3-q21.1, a region of about 6 Mb and 25 genes. Among these, the most outstanding is ATRX, the causative gene of X-linked alpha-thalassemia/mental retardation. ATRX belongs to the growing list of genes implied in chromatin remodeling causing ID. Many these genes, such as MECP2, are dose-sensitive so that not only deletions and point mutations, but also duplications cause ID. Both patients have severe ID, absent expressive speech, early hypotonia, behavior problems (hyperactivity, repetitive self-stimulatory behavior), postnatal growth deficiency, microcephaly, micrognathia, cryptorchidism, low-set, posteriorly angulated ears, and downslanting palpebral fissures. These findings are also usually present among patients with loss-of-function mutations of the ATRX gene. Completely skewed X inactivation was observed in the only informative carrier mother, a constant finding among female carriers of inactivating point mutations of this gene. Participation of other duplicated genes cannot be excluded; nevertheless we propose that the increased dosage of ATRX is the major pathogenic mechanism of this X-linked disorder, a syndrome reminiscent of MECP2 duplication.


Assuntos
Cromossomos Humanos X , DNA Helicases/genética , Duplicação Gênica , Deficiência Intelectual/genética , Retardo Mental Ligado ao Cromossomo X/genética , Proteínas Nucleares/genética , Adolescente , Criança , Feminino , Humanos , Masculino , Mutação , Inativação do Cromossomo X , Proteína Nuclear Ligada ao X , Talassemia alfa/genética
20.
Med Clin (Barc) ; 142(12): 531-7, 2014 Jun 16.
Artigo em Espanhol | MEDLINE | ID: mdl-23790573

RESUMO

BACKGROUND AND OBJECTIVE: An important proportion of neurodevelopmental disorders (NDDs) results from unbalanced genomic alterations (duplication or deletion). These chromosomal rearrangements may be considered as de novo, despite they arise as a result of a balanced rearrangement not detected in a phenotypically normal parent. Therefore, if the rearrangements are inherited, the recurrence risk and the genetic counseling of these cases change radically. Fluorescence in situ hybridization (FISH) is a technique that allows detecting both balanced and unbalanced rearrangements, identifying also the location of duplicated segments. We tried to locate in the genome the duplicated segments detected in patients with NDDs in order to identify those cases due to inherited rearrangements. PATIENTS AND METHOD: The study was conducted in 13 patients with NDDs and genomic duplications detected by compared genomic hybridization-array (CGH-array). Two approaches of FISH technique were taken: hybridization with painting chromosome probes and with specific probes for each duplication. RESULTS: In the studied series of 13 patients with duplication, 11 patients were found to carry tandem duplications, one with an intrachromosomal insertional translocation, and another with an interchromosomal insertional translocation. Therefore, 2 of the duplications considered de novo were actually an unbalanced rearrangement inherited from a parent who is a balanced carrier. CONCLUSION: The results illustrate the need to characterize by FISH technique the rearrangements that are detected by CGH-array to identify those cases with a high risk of recurrence.


Assuntos
Duplicação Cromossômica , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Testes Genéticos/métodos , Hibridização in Situ Fluorescente , Doenças do Sistema Nervoso/genética , Criança , Pré-Escolar , Humanos , Masculino , Linhagem , Risco , Translocação Genética
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