RESUMO
Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remains limited. Opportunely, several implementation studies and programs have been initiated over recent years. This article presents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undetermined collective clinical utility of implementing a panel of PGx-markers into routine care, because the evidence base is currently limited to specific, individual drug-gene pairs. The Ubiquitous Pharmacogenomics (U-PGx) Consortium, which has been funded by the European Commission's Horizon-2020 program, aims to address this unmet need. In a prospective, block-randomized, controlled clinical study (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions [PREPARE]), pre-emptive genotyping of a panel of clinically relevant PGx-markers, for which guidelines are available, will be implemented across healthcare institutions in seven European countries. The impact on patient outcomes and cost-effectiveness will be investigated. The program is unique in its multicenter, multigene, multidrug, multi-ethnic, and multihealthcare system approach.
Assuntos
Testes Farmacogenômicos/métodos , Testes Farmacogenômicos/estatística & dados numéricos , Projetos de Pesquisa , Biomarcadores , Análise Custo-Benefício , Registros Eletrônicos de Saúde/organização & administração , Europa (Continente) , Genótipo , Humanos , Testes Farmacogenômicos/economia , Testes Farmacogenômicos/tendências , Guias de Prática Clínica como Assunto , Medicina de Precisão/métodos , Estudos Prospectivos , Resultado do TratamentoRESUMO
The human cytomegalovirus (HCMV) is suspected to increase tumour malignancy by infection of cancer and/or stroma cells (oncomodulation). So far, oncomodulatory mechanisms have been attributed to the presence of HCMV and direct action of its gene products on cancer cells. Here, we investigated whether the prolonged presence of HCMV can result in the irreversible selection of a cancer cell population with increased malignancy. The neuroblastoma cell line UKF-NB-4 was long-term (200 passages) infected with the HCMV strain Hi91 (UKF-NB-4(Hi)) before virus eradication using ganciclovir (UKF-NB-4(HiGCV)). Global gene expression profiling of UKF-NB-4, UKF-NB-4(Hi) and UKF-NB-4(HiGCV) cells and subsequent bioinformatic signal transduction pathway analysis revealed clear differences between UKF-NB-4 and UKF-NB-4(Hi), as well as between UKF-NB-4 and UKF-NB-4(HiGCV) cells, but only minor differences between UKF-NB-4(Hi) and UKF-NB-4(HiGCV) cells. Investigation of the expression of a subset of five genes in different chronically HCMV-infected cell lines before and after virus eradication suggested that long-term HCMV infection reproducibly causes specific changes. Array comparative genomic hybridisation showed virtually the same genomic differences for the comparisons UKF-NB-4(Hi)/UKF-NB-4 and UKF-NB-4(HiGCV)/UKF-NB-4. UKF-NB-4(Hi) cells are characterised by an increased invasive potential compared with UKF-NB-4 cells. This phenotype was completely retained in UKF-NB-4(HiGCV) cells. Moreover, there was a substantial overlap in the signal transduction pathways that differed significantly between UKF-NB-4(Hi)/UKF-NB-4(HiGCV) and UKF-NB-4 cells and those differentially regulated between tumour tissues from neuroblastoma patients with favourable or poor outcome. In conclusion, we present the first experimental evidence that long-term HCMV infection can result in the selection of tumour cell populations with enhanced malignancy.
RESUMO
BACKGROUND: Mutations and deletions of the homeobox transcription factor gene SHOX are known to cause short stature. The authors have analysed SHOX enhancer regions in a large cohort of short stature patients to study the importance of regulatory regions in developmentally relevant genes like SHOX. METHODS: The authors tested for the presence of copy number variations in the pseudoautosomal region of the sex chromosomes in 735 individuals with idiopathic short stature and compared the results to 58 cases with Leri-Weill syndrome and 100 normal height controls, using fluorescence in situ hybridisation (FISH), single nucleotide polymorphism (SNP), microsatellites, and multiplex ligand dependent probe amplification (MLPA) analysis. RESULTS: A total of 31/735 (4.2%) microdeletions were identified in the pseudoautosomal region in patients with idiopathic short stature; eight of these microdeletions (8/31; 26%) involved only enhancer sequences residing a considerable distance away from the gene. In 58 Leri-Weill syndrome patients, a total of 29 microdeletions were identified; almost half of these (13/29; 45%) involve enhancer sequences and leave the SHOX gene intact. These deletions were absent in 100 control persons. CONCLUSION: The authors conclude that enhancer deletions in the SHOX gene region are a relatively frequent cause of growth failure in patients with idiopathic short stature and Leri-Weill syndrome. The data highlights the growing recognition that regulatory sequences are of crucial importance in the genome when diagnosing and understanding the aetiology of disease.
Assuntos
Cromossomos Humanos X , Cromossomos Humanos Y , Deleção de Genes , Transtornos do Crescimento/genética , Proteínas de Homeodomínio/genética , Criança , Pré-Escolar , Mapeamento Cromossômico , Estudos de Coortes , DNA/química , DNA/genética , Feminino , Dosagem de Genes , Humanos , Hibridização in Situ Fluorescente , Masculino , Repetições de Microssatélites/genética , Polimorfismo de Nucleotídeo Único/genética , Sequências Reguladoras de Ácido Nucleico , Proteína de Homoeobox de Baixa EstaturaRESUMO
We report on a 30-year-old man with azoospermia, primary hypogonadism and minor dysmorphic features who carried a balanced insertional chromosome translocation inv ins (2p24;4q28.3q31.22)de novo. Molecular cytogenetic analyses of the chromosome breakpoints revealed the localization of the breakpoint in 4q28.3 between BACs RP11-143E9 and RP11-285A15, an interval that harbours the PCDH10 gene. In 4q31.22, a breakpoint-spanning clone (RP11-6L6) was identified which contains the genes LSM6 and SLC10A7. On chromosome 2, BACs RP11-531P14 and RP11-360O18 flank the breakpoint in 2p24, a region void of known genes. In conclusion, the chromosome aberration of this patient suggests a gene locus for primary hypogonadism in 2p24, 4q28.3 or 4q31.2, and three possible candidate genes (LSM6, SLC10A7 and PCDH10) were identified by breakpoint analyses.
Assuntos
Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 4/genética , Hipogonadismo/genética , Adulto , Caderinas/genética , Humanos , Hibridização in Situ Fluorescente , Masculino , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Protocaderinas , Proteínas de Ligação a RNA/genética , Simportadores/genética , Translocação GenéticaRESUMO
We performed a systematic study on the frequency of point mutations and deletions of the gene GCH1 in dopa-responsive dystonia (DRD). A total of 136 dystonia patients were studied. Fifty of these had a sustained response to oral L-Dopa therapy (group 1: definite diagnosis of DRD), whereas the response to L-Dopa was incomplete or not tested in 86 patients (group 2: possible diagnosis of DRD). We found a GCH1 point mutation in 27 patients of group 1 (54%) and in four patients of group 2 (5%). Of these, nine single and one double mutation have not been described before. GCH1 deletions were detected in four patients of group 1 (8%) and in one patient of group 2 (1%). Among GCH1 point-mutation-negative patients with a definite diagnosis of DRD (group 1), the frequency of GCH1 deletions was 17% (4/23). We conclude that GCH1 deletion analysis should be incorporated into the routine molecular diagnosis of all patients with DRD with a sustained response to L-Dopa.
Assuntos
Antiparkinsonianos/uso terapêutico , Deleção Cromossômica , Distúrbios Distônicos/genética , GTP Cicloidrolase/genética , Frequência do Gene , Levodopa/uso terapêutico , Mutação Puntual , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas , Estudos de Coortes , Análise Mutacional de DNA , Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/tratamento farmacológico , Feminino , Genes Dominantes , Humanos , Lactente , Masculino , Repetições de Microssatélites , Penetrância , Análise de Sequência de ProteínaRESUMO
In the differential diagnosis of thrombophilic disorders genotyping of prothrombin and factor V are nowadays performed as a routine analysis. In the following we describe the unusual results of the mutation screening using melting point analysis for two patients and the consecutive detection of the mutation C20209T by sequencing the corresponding gene fragments. The molecular result is discussed with special respect to the medical history, ethnic background and clinical findings of both patients.
Assuntos
Análise Mutacional de DNA/métodos , Temperatura Alta , Desnaturação de Ácido Nucleico/genética , Mutação Puntual , Protrombina/genética , Adulto , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase/instrumentação , Análise de Sequência de DNA/métodos , Trombofilia/diagnósticoRESUMO
Dopa responsive dystonia (DRD) is an autosomal dominant dystonia caused by mutations in the gene GCH1 in about 50% of cases. GCH1 codes for GTP cyclohydrolase I, a rate limiting enzyme in the synthesis of tetrahydrobiobterin (BH(4)) from GTP. There is reduced penetrance and pronounced variation in expressivity of GCH1 mutations in families with DRD. Correlations between given mutations in GCH1 and phenotypes cannot be established. Mutations in GCH1 appear to function as dominant-negatives but the exact mechanism remains unclear. Additional open questions in DRD include the molecular mechanisms resulting in highly variable expressivity of symptoms and the more likely occurrence of symptoms in a female than in a male carrier of a GCH1 mutation.
Assuntos
Biopterinas/análogos & derivados , Biopterinas/biossíntese , Distonia/tratamento farmacológico , Distonia/genética , GTP Cicloidrolase/genética , Mutação/genética , Transtornos Cromossômicos/tratamento farmacológico , Transtornos Cromossômicos/enzimologia , Transtornos Cromossômicos/genética , Dopamina/biossíntese , Dopamina/deficiência , Distonia/enzimologia , Feminino , Humanos , Masculino , Fatores SexuaisRESUMO
Surgical correction of craniosynostosis is usually performed according to standard procedures. However, a standard for clinical examination and report of findings for patients with craniosynostosis does not exist as yet. To compare findings from different hospitals, a documentation system was developed by a national craniosynostosis group. This system comprises a two-page document, clinical photographs, radiographs, CT scans, anthropometric measurements and molecular genetic findings. Data from craniosynostosis patients collected from participating hospitals are stored in a database, which facilitates online access. The documentation system was developed in cooperation with the group during 3 years since 1996. It was evaluated as being practicable and reliable and enables a comparability of findings reported in different hospitals. Molecular genetic analysis was found to support the investigation of patients with craniosynostosis and should therefore be integrated in the clinical evaluation.
Assuntos
Craniossinostoses/diagnóstico , Prontuários Médicos/normas , Antropometria , Cefalometria , Bases de Dados como Assunto , Diagnóstico por Imagem , Estudos de Viabilidade , Controle de Formulários e Registros , Humanos , Sistemas Computadorizados de Registros Médicos , Biologia Molecular , Sistemas On-Line , Fotografação , Exame Físico , Tomografia Computadorizada por Raios XRESUMO
Analysis of the gene GCH1 in 58 patients with dystonia and a positive response to L-dopa revealed mutations in 30 individuals from 22 families. Thirteen of the mutations observed were familial, three occurred de novo, and inheritance could not be determined in six cases. There was no mutation in the promoter region of GCH1 in any patient. The doses of L-dopa given to members of the two groups were not significantly different.
Assuntos
Di-Hidroxifenilalanina/uso terapêutico , Distonia/tratamento farmacológico , Distonia/genética , GTP Cicloidrolase/genética , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genéticaRESUMO
BACKGROUND AND PURPOSE: Jugular foraminal stenosis (JFS) or atresia (JFA) with collateral emissary veins (EV) has been documented in syndromic craniosynostosis. Disruption of EV during surgery can produce massive hemorrhage. Our purpose was to describe the prevalence of prominent basal emissary foramina (EF), which transmit enlarged EV, in syndromic craniosynostosis. Our findings were correlated with phenotypic and molecular diagnoses. METHODS: We reviewed the medical records and imaging examinations of 33 patients with syndromic craniosynostosis and known fibroblast growth factor receptor (FGFR) mutations. All patients underwent CT and 14 MR imaging. The cranial base was assessed for size of occipitomastoid EF and jugular foramina (JF). Vascular imaging studies were available from 12 patients. A control group (n = 76) was used to establish normal size criteria for JF and EF. RESULTS: Phenotypic classification included Crouzon syndrome (n = 10), crouzonoid features with acanthosis nigricans (n = 3), Apert syndrome (n = 10), Pfeiffer syndrome (n = 4), and clinically unclassifiable bilateral coronal synostosis (n = 6). EF > or = 3 mm in diameter and JFS or JFA were identified in 23 patients with various molecular diagnoses. Vascular imaging in patients with JFS or JFA and enlarged EF revealed atresia or stenosis of the jugular veins and enlarged basal EV. JFA was seen in all patients with the FGFR3 mutation with crouzonoid features and acanthosis nigricans. Four patients had prominent EF without JFS. Six patients had normal JF and lacked enlarged EF. CONCLUSION: Enlarged basal EF are common in syndromic craniosynostosis and are usually associated with JFS or JFA. Bilateral basilar venous atresia is most common in patients with the FGFR3 ala391glu mutation and crouzonoid features with acanthosis nigricans, but may be found in patients with FGFR2 mutations. Skull base vascular imaging should be obtained in patients with syndromic craniosynostosis with enlarged EF.
Assuntos
Craniossinostoses/diagnóstico , Base do Crânio/diagnóstico por imagem , Base do Crânio/patologia , Acrocefalossindactilia/diagnóstico , Adolescente , Adulto , Veias Cerebrais/diagnóstico por imagem , Veias Cerebrais/patologia , Criança , Pré-Escolar , Disostose Craniofacial/diagnóstico , Craniossinostoses/diagnóstico por imagem , Craniossinostoses/genética , Feminino , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Mutação , Fenótipo , Receptores de Fatores de Crescimento de Fibroblastos/genética , Tomografia Computadorizada por Raios XRESUMO
UNLABELLED: We report a female newborn with characteristic signs of Antley-Bixler syndrome (ABS) such as midface hypoplasia, radiohumeral synostosis and multiple joint contractures. The newborn also presented ambiguous genitalia, stage Prader V, and congenital adrenal hyperplasia. The mother experienced midterm virilization due to a pregnancy luteoma. Her elevated androgen levels and virilization symptoms normalized post partum without treatment. The newborn had elevated serum testosterone and 17-OH-progesterone levels which remained elevated because of a 21-hydroxylase deficiency. The child's treatment in order of priority was: hydrocortisone substitution, craniofacial/skeletal anomaly management and surgical correction of the external genitalia. Mutations in the genes for fibroblast growth factor (FGF) 8 and receptors FGFR1, FGFR2, and FGFR3 were not detected. CONCLUSION: A newborn girl with manifestations of the Antley-Bixler syndrome showed severe virilization probably caused by the association of a mild 21-hydroxylase deficiency and maternal hyperandrogenism due to a pregnancy luteoma. Abnormalities of androgen metabolism may be responsible for virilization reported in other cases of the Antley-Bixler syndrome.
Assuntos
Craniossinostoses , Transtornos do Desenvolvimento Sexual , Luteoma , Neoplasias Ovarianas , Complicações Neoplásicas na Gravidez , Hiperplasia Suprarrenal Congênita/complicações , Adulto , Transtornos do Desenvolvimento Sexual/sangue , Transtornos do Desenvolvimento Sexual/metabolismo , Feminino , Humanos , Hidrocortisona/deficiência , Recém-Nascido , Gravidez , Síndrome , Virilismo/metabolismoAssuntos
Controle de Formulários e Registros/organização & administração , Oftalmologia/organização & administração , Serviços Terceirizados/organização & administração , Mecanismo de Reembolso/organização & administração , Contas a Pagar e a Receber , Documentação , Eficiência Organizacional , Humanos , Estados UnidosRESUMO
Paragangliomas (glomus tumors) are slowly growing, mostly benign tumors of the parasympathetic ganglia which most frequently occur in the head and neck region. Between 10% and 50% of cases are familial and follow an autosomal dominant mode of inheritance. The trait is maternally imprinted and exclusively transmitted through the paternal line. To date, two loci have been implicated in this disorder: one at 11q23 (PGL1), the other one at 11q13 (PGL2). We have analyzed a large German family with hereditary paraganglioma, but no evidence of maternal imprinting. By linkage analysis with markers flanking both PGL1 and PGL2, we demonstrate that the trait does not segregate with either of the loci at 11q. Our findings show that a third locus, PGL3, can be involved in hereditary paraganglioma.
Assuntos
Cromossomos Humanos Par 11 , Saúde da Família , Gânglios Parassimpáticos , Ligação Genética , Paraganglioma/genética , Neoplasias do Sistema Nervoso Periférico/genética , Idoso , Primers do DNA , Feminino , Marcadores Genéticos , Impressão Genômica , Alemanha , Neoplasias de Cabeça e Pescoço/genética , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
The authors performed a prospective study evaluating molecular diagnosis in patients with bilateral coronal synostosis. The patients were divided into two groups: (1) those clinically classified as having Apert, Crouzon, or Pfeiffer syndrome and (2) those clinically unclassified and labeled as having brachycephaly. Blood samples were drawn for genomic DNA analysis from 57 patients from 1995 to 1997. Polymerase chain reactions were performed using primers flanking exons in FGFR 1, 2, and 3. Each exon was screened for mutations using single-strand confirmation polymorphism, and mutations were identified by DNA sequencing. Mutations in FGFR2 or FGFR3 were found in all patients (n = 38) assigned a phenotypic (eponymous) diagnosis. All Apert syndrome patients (n = 13) carried one of the two known point mutations in exon 7 of FGFR2 (Ser252Trp and Pro253Arg). Twenty-five patients were diagnosed as having either Crouzon or Pfeiffer syndrome. Five patients with Crouzon syndrome of variable severity had mutations in exon 7 of FGFR2. Fifteen patients (12 with Crouzon, 3 with Pfeiffer) had a mutation in exon 9 of FGFR2, many of which involved loss or gain of a cysteine residue. A wide phenotypic range was observed in patients with identical mutations, including those involving cysteine. Two patients labeled as having Crouzon syndrome had the Pro250Arg mutation in exon 7 of FGFR3. All three patients with the crouzonoid phenotype and acanthosis nigricans had the same mutation in exon 10 of FGFR3 (Ala391Glu). This is a distinct disorder, characterized by jugular foraminal stenosis, Chiari I anomaly, and intracranial venous hypertension. Mutations were found in 14 of 19 clinically unclassifiable patients. Three mutations were in exon 9, and one was in the donor splice site of intron 9 on FGFR2. The most common mutation discovered in this group was Pro250Arg in exon 7 of FGFR3. These patients (n = 10) had either bilateral or unilateral coronal synostosis, minimal midfacial hypoplasia with class I or class II occlusion, and minor brachysyndactyly. No mutations in FGFR 1, 2, or 3 were detected in five patients with nonspecific brachycephaly. In conclusion, a molecular diagnosis was possible in all patients (n = 38) given a phenotypic (eponymous) diagnosis. Different phenotypes observed with identical mutations probably resulted from modulation by their genetic background. A molecular diagnosis was made in 74 percent of the 19 unclassified patients in this series; all mutations were in FGFR2 or FGFR3. Our data and those of other investigators suggest that we should begin integrating molecular diagnosis with phenotypic diagnosis of craniosynostoses in studies of natural history and dysmorphology and in analyses of surgical results.
Assuntos
Craniossinostoses/diagnóstico , Análise Mutacional de DNA , Reação em Cadeia da Polimerase , Criança , Pré-Escolar , Craniossinostoses/classificação , Craniossinostoses/genética , Éxons , Feminino , Humanos , Lactente , Íntrons , Masculino , Fenótipo , Receptores Proteína Tirosina Quinases/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Receptores de Fatores de Crescimento de Fibroblastos/genéticaRESUMO
The authors report a mutation in exon 5 of GCH1 in a patient with adult-onset oromandibular dystonia and no obvious family history of dystonia. The patient responded positively to treatment with L-dopa. These findings demonstrate that GCH1 mutations must be considered even in patients with dystonic symptoms not typical of dopa-responsive dystonia.