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1.
Am J Hum Genet ; 105(3): 640-657, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31402090

RESUMO

The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. FBXW11 encodes an F-box protein, part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degradation and thus fundamental to many protein regulatory processes. FBXW11 targets include ß-catenin and GLI transcription factors, key mediators of Wnt and Hh signaling, respectively, critical to digital, neurological, and eye development. Structural analyses indicate affected residues cluster at the surface of the loops of the substrate-binding domain of FBXW11, and the variants are predicted to destabilize the protein and/or its interactions. In situ hybridization studies on human and zebrafish embryonic tissues demonstrate FBXW11 is expressed in the developing eye, brain, mandibular processes, and limb buds or pectoral fins. Knockdown of the zebrafish FBXW11 orthologs fbxw11a and fbxw11b resulted in embryos with smaller, misshapen, and underdeveloped eyes and abnormal jaw and pectoral fin development. Our findings support the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw.

2.
Neuromuscul Disord ; 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30409445

RESUMO

Immunoglobulin-helicase-µ-binding protein 2 (IGHMBP2) mutations are associated with partial continuum between two extremes of rapidly lethal disorder of spinal muscular atrophy with respiratory distress type 1 (SMARD1), with infantile axonal neuropathy, diaphragmatic weakness and commonly death before 1 year of age, and Charcot-Marie-Tooth disease (CMT) type 2S with slowly progressive weakness and sensory loss but no significant respiratory compromise. We present an atypical case of CMT2S. A 9 month old boy presented with bilateral feet deformities and axonal neuropathy. Genetic testing revealed two heterozygous variants in the IGHMBP2 gene: c.1156 T > C p.(Trp386Arg) in exon 8 and c.2747G > A p.(Cys916Tyr) in exon 14, that were inherited from his father and mother respectively. At 9 years, he developed diaphragmatic weakness, following which he was established on non-invasive ventilation. Our case emphasizes the importance of life long respiratory surveillance for patients with CMT2S and expands the phenotype of this condition.

3.
Neurology ; 88(13): 1226-1234, 2017 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-28251916

RESUMO

OBJECTIVE: To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England. METHODS: Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients). RESULTS: The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62-2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy. CONCLUSIONS: Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies.


Assuntos
Doença de Charcot-Marie-Tooth/epidemiologia , Heterogeneidade Genética , Neuropatia Hereditária Motora e Sensorial/epidemiologia , Neuropatia Hereditária Motora e Sensorial/genética , Mutação/genética , Adolescente , Adulto , Idoso , Análise de Variância , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Estudos de Coortes , Conexinas/genética , Análise Mutacional de DNA , Eletromiografia , Inglaterra/epidemiologia , Saúde da Família , Feminino , GTP Fosfo-Hidrolases/genética , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Proteínas da Mielina/genética , Condução Nervosa/genética , Adulto Jovem
4.
Eur J Hum Genet ; 24(10): 1377-87, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27165005

RESUMO

Molecular genetic testing for the 11p15-associated imprinting disorders Silver-Russell and Beckwith-Wiedemann syndrome (SRS, BWS) is challenging because of the molecular heterogeneity and complexity of the affected imprinted regions. With the growing knowledge on the molecular basis of these disorders and the demand for molecular testing, it turned out that there is an urgent need for a standardized molecular diagnostic testing and reporting strategy. Based on the results from the first external pilot quality assessment schemes organized by the European Molecular Quality Network (EMQN) in 2014 and in context with activities of the European Network of Imprinting Disorders (EUCID.net) towards a consensus in diagnostics and management of SRS and BWS, best practice guidelines have now been developed. Members of institutions working in the field of SRS and BWS diagnostics were invited to comment, and in the light of their feedback amendments were made. The final document was ratified in the course of an EMQN best practice guideline meeting and is in accordance with the general SRS and BWS consensus guidelines, which are in preparation. These guidelines are based on the knowledge acquired from peer-reviewed and published data, as well as observations of the authors in their practice. However, these guidelines can only provide a snapshot of current knowledge at the time of manuscript submission and readers are advised to keep up with the literature.


Assuntos
Síndrome de Beckwith-Wiedemann/genética , Cromossomos Humanos Par 11/genética , Testes Genéticos/normas , Guias de Prática Clínica como Assunto , Síndrome de Silver-Russell/genética , Síndrome de Beckwith-Wiedemann/diagnóstico , Europa (Continente) , Impressão Genômica , Humanos , Síndrome de Silver-Russell/diagnóstico , Sociedades Médicas
5.
BMC Med Genet ; 16: 84, 2015 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-26392352

RESUMO

BACKGROUND: Inherited peripheral neuropathy (IPN) is a clinically and genetically heterogeneous group of disorders with more than 90 genes associated with the different subtypes. Sequential gene screening is gradually being replaced by next generation sequencing (NGS) applications. METHODS: We designed and validated a targeted NGS panel assay including 56 genes associated with known causes of IPN. We report our findings following NGS panel testing of 448 patients with different types of clinically-suspected IPN. RESULTS: Genetic diagnosis was achieved in 137 patients (31%) and involved 195 pathogenic variants in 31 genes. 93 patients had pathogenic variants in genes where a resulting phenotype follows dominant inheritance, 32 in genes where this would follow recessive inheritance, and 12 presented with X-linked disease. Almost half of the diagnosed patients (64) had a pathogenic variant either in genes not previously available for routine diagnostic testing in a UK laboratory (50 patients) or in genes whose primary clinical association was not IPN (14). Seven patients had a pathogenic variant in a gene not hitherto indicated from their phenotype and three patients had more than one pathogenic variant, explaining their complex phenotype and providing information essential for accurate prediction of recurrence risks. CONCLUSIONS: Our results demonstrate that targeted gene panel testing is an unbiased approach which overcomes the limitations imposed by limited existing knowledge for rare genes, reveals high heterogeneity, and provides high diagnostic yield. It is therefore a highly efficient and cost effective tool for achieving a genetic diagnosis for IPN.


Assuntos
Testes Genéticos/métodos , Variação Genética , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/patologia , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Linhagem , Doenças do Sistema Nervoso Periférico/genética , Fenótipo , Reprodutibilidade dos Testes , Análise de Sequência de DNA/economia , Análise de Sequência de DNA/métodos
6.
J Neurol ; 262(8): 1899-908, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26032230

RESUMO

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy with heterogeneous clinical presentation and genetic background. The axonal form (CMT2) is characterised by decreased action potentials indicating primary axonal damage. The underlying pathology involves axonal degeneration which is supposed to be related to axonal protein dysfunction caused by various gene mutations. The overlapping clinical manifestation of CMT2 with distal hereditary motor neuropathy (dHMN) and intermediate CMT causes further diagnostic difficulties. Aminoacyl-tRNA synthetases have been implicated in the pathomechanism of CMT2. They have an essential role in protein translation by attaching amino acids to their cognate tRNAs. To date six families have been reported worldwide with dominant missense alanyl-tRNA synthetase (AARS) mutations leading to clinically heterogeneous axonal neuropathies. The pathomechanism of some variants could be explained by impaired amino acylation activity while other variants implicating an editing defect need to be further investigated. Here, we report a cohort of six additional families originating from the United Kingdom and Ireland with dominant AARS-related neuropathies. The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated. Nerve conduction studies revealed significant demyelination accompanying the axonal lesion in motor and sensory nerves. Five families have the c.986G>A, p.(Arg329His) variant, further supporting that this is a recurrent loss of function variant. The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly). We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies.


Assuntos
Aminoacil-tRNA Sintetases/genética , Neuropatia Hereditária Motora e Sensorial/genética , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Adulto , Idoso , Axônios/patologia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genótipo , Humanos , Irlanda , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Reino Unido , Adulto Jovem
7.
Neuromuscul Disord ; 25(6): 516-21, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25900305

RESUMO

Mutations in the transient receptor potential vanilloid 4 (TRPV4) gene have been associated with autosomal dominant skeletal dysplasias and peripheral nervous system syndromes (PNSS). PNSS include Charcot-Marie-Tooth disease (CMT) type 2C, congenital spinal muscular atrophy and arthrogryposis and scapuloperoneal spinal muscular atrophy. We report the clinical, electrophysiological and muscle biopsy findings in two unrelated patients with two novel heterozygous missense mutations in the TRPV4 gene. Whole exome sequencing was carried out on genomic DNA using Illumina Truseq(TM) 62Mb exome capture. Patient 1 harbours a de novo c.805C > T (p.Arg269Cys) mutation. Clinically, this patient shows signs of both scapuloperoneal spinal muscular atrophy and skeletal dysplasia. Patient 2 harbours a novel c.184G > A (p.Asp62Asn) mutation. While the clinical phenotype is compatible with CMT type 2C with the patient's muscle harbours basophilic inclusions. Mutations in the TRPV4 gene have a broad phenotypic variability and disease severity and may share a similar pathogenic mechanism with Heat Shock Protein related neuropathies.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Nanismo/genética , Atrofia Muscular Espinal/genética , Osteocondrodisplasias/genética , Canais de Cátion TRPV/genética , Doença de Charcot-Marie-Tooth/patologia , Criança , Nanismo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Muscular Espinal/patologia , Mutação de Sentido Incorreto , Osteocondrodisplasias/patologia , Fenótipo
8.
In Vivo ; 26(1): 165-72, 2012 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22210734

RESUMO

BACKGROUND/AIM: Thrombophilia is a multifactorial predisposition for thromboembolism affecting about a tenth of any population. We investigated whether genetic counseling combined with molecular testing for two common dominant mutations (coagulation factor V Leiden and prothrombin G20210A) may increase prevention of venous thromboembolic incidents in individuals with a positive family history compared to the general population. PATIENTS AND METHODS: Mutation detection was carried out by Restriction Fragment Length Polymorphism analysis in DNA samples of 96 unrelated healthy Greeks (group A) who asked for genetic counseling for various reasons and had at least two relatives with thromboembolic incidents and 100 unrelated healthy Greeks (group B). RESULTS: In group A, both mutations were detected at five-fold higher frequencies (33.33% for Leiden and 19.79% for G20210A) compared to group B, which had frequencies typically found in the Greek population (6% and 4%, respectively). CONCLUSION: In populations with a high prevalence for these two common mutations, genetic counseling and molecular testing of at-risk individuals may significantly increase prevention of thromboembolic disease.


Assuntos
Aconselhamento Genético/métodos , Testes Genéticos/métodos , Mutação , Tromboembolia/genética , Tromboembolia/prevenção & controle , Trombofilia/genética , Adulto , Análise Mutacional de DNA , Fator V/genética , Saúde da Família , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Fragmento de Restrição , Protrombina/genética , Fatores de Risco , Tromboembolia/diagnóstico , Adulto Jovem
9.
Am J Hum Genet ; 89(2): 308-12, 2011 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-21820100

RESUMO

Charcot-Marie-Tooth disease is characterized by length-dependent axonal degeneration with distal sensory loss and weakness, deep-tendon-reflex abnormalities, and skeletal deformities. It is caused by mutations in more than 40 genes. We investigated a four-generation family with 23 members affected by the axonal form (type 2), for which the common causes had been excluded by Sanger sequencing. Exome sequencing of three affected individuals separated by eight meioses identified a single shared novel heterozygous variant, c.917A>G, in DYNC1H1, which encodes the cytoplasmic dynein heavy chain 1 (here, novel refers to a variant that has not been seen in dbSNP131or the August 2010 release of the 1000 Genomes project). Testing of six additional affected family members showed cosegregation and a maximum LOD score of 3.6. The shared DYNC1H1 gene variant is a missense substitution, p.His306Arg, at a highly conserved residue within the homodimerization domain. Three mouse models with different mutations within this domain have previously been reported with age-related progressive loss of muscle bulk and locomotor ability. Cytoplasmic dynein is a large multisubunit motor protein complex and has a key role in retrograde axonal transport in neurons. Our results highlight the importance of dynein and retrograde axonal transport in neuronal function in humans.


Assuntos
Axônios/patologia , Doença de Charcot-Marie-Tooth/genética , Dineínas do Citoplasma/genética , Éxons/genética , Genes Dominantes/genética , Mutação/genética , Adulto , Animais , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Camundongos , Linhagem , Adulto Jovem
10.
Genet Test Mol Biomarkers ; 14(2): 189-92, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20059378

RESUMO

A variety of techniques have been developed for screening the GJB2 gene for known and unknown mutations, especially the most common mutation in the Caucasian population, the c.35delG. Other mutations that have been so far characterized in the GJB2 gene seem to have different geographical distributions, and therefore there is an interest in identifying recurrent mutations specific for each population and developing easy and rapid screening techniques. Here we present easy screening protocols for already identified recurrent mutations in the Greek population. Developing easy, rapid, and cost-effective screening methods will facilitate the detection of GJB2 recurrent mutation carriers, at large, in the Greek population.


Assuntos
Conexinas/genética , Triagem de Portadores Genéticos/métodos , Testes Genéticos/métodos , Perda Auditiva/genética , Mutação , Sequência de Bases , Conexina 26 , Análise Custo-Benefício , Primers do DNA/genética , Surdez/genética , Feminino , Frequência do Gene , Genes Recessivos , Testes Genéticos/economia , Grécia , Perda Auditiva Neurossensorial/genética , Humanos , Masculino , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Deleção de Sequência
11.
Prenat Diagn ; 26(3): 258-61, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16475234

RESUMO

OBJECTIVE: We report an atypical case of a fetus presenting with a combined achondroplasia and multiple craniosynostosis phenotype. METHODS: Sonographic monitoring in conjunction with molecular genetic analysis was performed in a 32-gestational weeks fetus. RESULTS: Sonographic findings were consistent with a diagnosis of achondroplasia associated with multiple-suture synostosis. The most common G380R FGFR3 achondroplasia mutation was detected. CONCLUSION: The most common achondroplasia mutation should be considered for prenatal DNA testing in cases with ultrasound findings of achondroplasia and multiple-suture synostosis. This is crucial for the genetic counselling and perinatal management of the fetus.


Assuntos
Acondroplasia/diagnóstico por imagem , Craniossinostoses/diagnóstico por imagem , Doenças Fetais/diagnóstico por imagem , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Ultrassonografia Pré-Natal , Acondroplasia/genética , Adulto , Craniossinostoses/genética , Éxons , Feminino , Doenças Fetais/genética , Humanos , Mutação , Gravidez
12.
Genet Test ; 8(3): 276-80, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15727251

RESUMO

We have screened 175 patients for molecular defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene using nondenaturing polyacrylamide gel electrophoresis (PAGE), denaturing gradient gel electrophoresis (DGGE), and sequencing. Six different mutations (F508del, G542X, 621+1G --> T, 2789+5G --> A, R1070Q, and S466X) accounted for 79.71% of CF alleles, with the F508del mutation showing a frequency of 72.28%. Another 12 mutations (R334W, 2184insA, I507del, 1525-1G --> A, E585X, R75X, M1I, 457TAT --> G, 574delA, 2723delTT, A120T, and 2907delTT) covered an additional 3.36%. A novel mutation (2723delTT) was found in one CF patient (F508del/2723delTT). Thus, a total of 18 mutations cover 82.57% of CF alleles. During our study, 72% of families at risk for having a CF child were found to be fully informative for prenatal diagnosis. Prenatal diagnosis was performed on 56 families; 76 analyses resulting in 16 affected, 38 carriers, and 22 healthy fetuses. These results imply that the molecular basis of CF in Serbia and Montenegro is highly heterogeneous, as is observed in other eastern and southern European populations. Because we detected more then 80% of CFTR alleles, results could be used for planning future screening and appropriate genetic counseling programs in our country.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/diagnóstico , Mutação/genética , Diagnóstico Pré-Natal , Alelos , Fibrose Cística/etnologia , Fibrose Cística/genética , Feminino , Frequência do Gene , Aconselhamento Genético , Humanos , Gravidez , Fatores de Risco , Iugoslávia
13.
Eur J Hum Genet ; 10(11): 694-8, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12404100

RESUMO

The clinical significance of trisomy 20 mosaicism detected prenatally remains uncertain due to the rarity of liveborn cases with inconsistent clinical findings, and lack of long-term follow-up and outcome. We describe a case of true trisomy 20 mosaicism in a liveborn girl with maternal uniparental isodisomy of chromosome 20 in the diploid blood cells. Trisomy 20 mosaicism was originally detected in amniotic fluid (98%) and was confirmed in the term placenta (100%), as well as in the blood (10%) and urine sediment (100%) of the neonate. There was intrauterine and postnatal growth retardation, but otherwise the newborn manifested no gross abnormalities. At 9 months of age moderate psychomotor retardation, central hypotonia with peripheral hypertonia, numerous minor morphogenetic variants, marked kyphosis, and extensive Mongolian spot were observed. To our knowledge this represents the first case of trisomy 20 mosaicism detected prenatally and confirmed in different tissues of the newborn, where uniparental disomy was demonstrated in the diploid cell line. The clinical and laboratory findings in our patient are compared with those of five previously reported cases of UPD20, suggesting that maternal UPD20 might be associated with a characteristic phenotype.


Assuntos
Cromossomos Humanos Par 20 , Mosaicismo , Trissomia , Dissomia Uniparental , Feminino , Marcadores Genéticos , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Transtornos Psicomotores/etiologia , Transtornos Psicomotores/genética
14.
Int J Pediatr Otorhinolaryngol ; 65(2): 101-8, 2002 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-12176179

RESUMO

OBJECTIVE: Mutations in the gene encoding the gap junction protein connexin 26 (GJB2) have been shown as a major contributor to prelingual, sensorineural, nonsyndromic, recessive deafness. One specific mutation, 35delG, has accounted for the majority of the mutations detected in the GJB2 gene in Caucasian populations. The aim of our study was to determine the prevalence and spectrum of GJB2 mutations in prelingual deafness in the Greek population. METHODS: In a collaboration with the major referral centers for childhood deafness in Greece, patients were examined by an extensive questionnaire to exclude syndromic forms and environmental causes of deafness and by allele-specific polymerase chain reaction (PCR) for the detection of the 35delG mutation. Patients heterozygous for the 35delG mutation were further analyzed by direct genomic sequencing of the coding region of the GJB2 gene. RESULTS: The 35delG mutation was found in 42.2% of the chromosomes in 45 familial cases of prelingual, nonsyndromic deafness (18 homozygotes and 2 heterozygotes) and in 30.6% of the chromosomes in 165 sporadic cases (45 homozygotes and 11 heterozygotes). Direct genomic sequencing in heterozygous patients revealed the L90P (2 alleles), W24X (2 alleles), R184P (2 alleles), and 291insA (1 allele) mutations. CONCLUSION: Mutations in the GJB2 gene are responsible for about one third of prelingual, sensorineural, nonsyndromic deafness in the Greek population, and allele-specific PCR is an easy screening method for the common 35delG mutation.


Assuntos
Conexinas/genética , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/genética , Mutação , Sequência de Bases , Pré-Escolar , Conexina 26 , Análise Mutacional de DNA , Feminino , Testes Genéticos , Genótipo , Grécia/epidemiologia , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase , Vigilância da População , Prevalência
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