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1.
Hum Mutat ; 35(9): 1092-100, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24924640

RESUMO

Marshall-Smith syndrome (MSS) is a very rare malformation syndrome characterized by typical craniofacial anomalies, abnormal osseous maturation, developmental delay, failure to thrive, and respiratory difficulties. Mutations in the nuclear factor 1/X gene (NFIX) were recently identified as the cause of MSS. In our study cohort of 17 patients with a clinical diagnosis of MSS, conventional sequencing of NFIX revealed frameshift and splice-site mutations in 10 individuals. Using multiplex ligation-dependent probe amplification analysis, we identified a recurrent deletion of NFIX exon 6 and 7 in five individuals. We demonstrate this recurrent deletion is the product of a recombination between AluY elements located in intron 5 and 7. Two other patients had smaller deletions affecting exon 6. These findings show that MSS is a genetically homogeneous Mendelian disorder. RT-PCR experiments with newly identified NFIX mutations including the recurrent exon 6 and 7 deletion confirmed previous findings indicating that MSS-associated mutant mRNAs are not cleared by nonsense-mediated mRNA decay. Predicted MSS-associated mutant NFIX proteins consistently have a preserved DNA binding and dimerization domain, whereas they grossly vary in their C-terminal portion. This is in line with the hypothesis that MSS-associated mutations encode dysfunctional proteins that act in a dominant negative manner.


Assuntos
Anormalidades Múltiplas/genética , Elementos Alu , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Éxons , Fatores de Transcrição NFI/genética , Displasia Septo-Óptica/genética , Deleção de Sequência , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/diagnóstico , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Anormalidades Craniofaciais/diagnóstico , Análise Mutacional de DNA , Fácies , Feminino , Expressão Gênica , Loci Gênicos , Humanos , Lactente , Masculino , Mutação , Fenótipo , RNA Mensageiro/genética , Displasia Septo-Óptica/diagnóstico , Adulto Jovem
2.
Eur J Hum Genet ; 32(5): 529-538, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38355963

RESUMO

It is believed that >95% of people with Lynch syndrome (LS) remain undiagnosed. Within the National Health Service (NHS) in England, formal guidelines issued in 2017 state that all colorectal cancers (CRC) should be tested for DNA Mismatch Repair deficiency (dMMR). We used a comprehensive population-level national dataset to analyse implementation of the agreed diagnostic pathway at a baseline point 2 years post-publication of official guidelines. Using real-world data collected and curated by the National Cancer Registration and Analysis Service (NCRAS), we retrospectively followed up all people diagnosed with CRC in England in 2019. Nationwide laboratory diagnostic data incorporated somatic (tumour) testing for dMMR (via immunohistochemistry or microsatellite instability), somatic testing for MLH1 promoter methylation and BRAF status, and constitutional (germline) testing of MMR genes. Only 44% of CRCs were screened for dMMR; these figures varied over four-fold with respect to geography. Of those CRCs identified as dMMR, only 51% underwent subsequent diagnostic testing. Overall, only 1.3% of patients with colorectal cancer had a germline MMR genetic test performed; up to 37% of these tests occurred outside of NICE guidelines. The low rates of molecular diagnostic testing in CRC support the premise that Lynch syndrome is underdiagnosed, with significant attrition at all stages of the testing pathway. Applying our methodology to subsequent years' data will allow ongoing monitoring and analysis of the impact of recent investment. If the diagnostic guidelines were fully implemented, we estimate that up to 700 additional people with LS could be identified each year.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Inglaterra , Neoplasias Colorretais/genética , Neoplasias Colorretais/diagnóstico , Feminino , Testes Genéticos/normas , Testes Genéticos/métodos , Masculino , Reparo de Erro de Pareamento de DNA , Proteína 1 Homóloga a MutL/genética , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/genética , Idoso , Adulto
3.
Am J Hum Genet ; 87(2): 189-98, 2010 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-20673863

RESUMO

By using a combination of array comparative genomic hybridization and a candidate gene approach, we identified nuclear factor I/X (NFIX) deletions or nonsense mutation in three sporadic cases of a Sotos-like overgrowth syndrome with advanced bone age, macrocephaly, developmental delay, scoliosis, and unusual facies. Unlike the aforementioned human syndrome, Nfix-deficient mice are unable to gain weight and die in the first 3 postnatal weeks, while they also present with a spinal deformation and decreased bone mineralization. These features prompted us to consider NFIX as a candidate gene for Marshall-Smith syndrome (MSS), a severe malformation syndrome characterized by failure to thrive, respiratory insufficiency, accelerated osseous maturation, kyphoscoliosis, osteopenia, and unusual facies. Distinct frameshift and splice NFIX mutations that escaped nonsense-mediated mRNA decay (NMD) were identified in nine MSS subjects. NFIX belongs to the Nuclear factor one (NFI) family of transcription factors, but its specific function is presently unknown. We demonstrate that NFIX is normally expressed prenatally during human brain development and skeletogenesis. These findings demonstrate that allelic NFIX mutations trigger distinct phenotypes, depending specifically on their impact on NMD.


Assuntos
Anormalidades Múltiplas/genética , Alelos , Códon sem Sentido/genética , Mutação/genética , Fatores de Transcrição NFI/genética , Estabilidade de RNA/genética , Adolescente , Adulto , Sequência de Bases , Criança , Cromossomos Humanos Par 19/genética , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Feminino , Regulação da Expressão Gênica , Testes Genéticos , Humanos , Hibridização In Situ , Masculino , Dados de Sequência Molecular , Fatores de Transcrição NFI/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Síndrome
4.
Am J Med Genet A ; 158A(5): 1014-9, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22438093

RESUMO

Congenital melanocytic nevi (CMN) are known to be associated with neurological abnormalities and melanoma, but have not been considered to be part of a developmental syndrome. The objective of this study was to test our clinical observation that children with CMN show more facial similarities than might be expected by coincidence. We selected facial photographs of 95 white Caucasian children with CMN from our database only on the basis of good neutral views, allowing careful evaluation of facial morphology. These were scored independently by two clinical geneticists using standardized categories and definitions for facial morphology. Prevalence of age-independent features was compared to established norms in a large population, and associations with cutaneous phenotype were investigated. CMN were found to be associated with characteristic facies, and 74% of children in this series had at least three typical features. The characteristic features were: wide or prominent forehead, apparent hypertelorism, eyebrow variants, periorbital fullness, small/short nose, narrow nasal ridge, broad nasal tip, broad or round face, full cheeks, prominent pre-maxilla, prominent/long philtrum, and everted lower lip. No association was found with the severity of cutaneous phenotype. We conclude that children with CMN often have a characteristic face. We propose the term "congenital melanocytic nevus syndrome" to describe this association.


Assuntos
Face/anormalidades , Melanoma/diagnóstico , Nevo Pigmentado/diagnóstico , Criança , Classificação , Humanos , Melanoma/congênito , Nevo Pigmentado/congênito , Fenótipo , Neoplasias Cutâneas , Síndrome
5.
Am J Med Genet A ; 152A(11): 2714-26, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20949508

RESUMO

Marshall-Smith syndrome (MSS) is a distinctive entity of unknown etiology with fewer than 50 patients described in the medical literature to date. Through an International collaboration and use of an online wiki to facilitate data collection and sharing, we further delineate the phenotype and natural history of this syndrome. We present 15 new patients, the oldest being 30 years, provide an update on four previously published cases, and compare all patients with other patients reported in literature. Main clinical features are moderate to severe developmental delay with absent or limited speech, unusual behavior, dysharmonic bone maturation, respiratory compromise secondary to upper airway obstruction, short stature, and kyphoscoliosis. Facial features are characteristic with high forehead, underdeveloped midface, proptosis, anteverted nares, and everted lips. Minor abnormalities of brain morphology such as hypoplasia of the corpus callosum are common. Mortality from respiratory complications is high, but airway support increasingly allows survival into adulthood. Array-CGH was performed on 12 of the cohort and no copy number variants of clear clinical relevance were identified. The present study is the first reported use of an online wiki to aid delineation of a genetic syndrome, and illustrates its value in collecting detailed data in rare conditions.


Assuntos
Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Anormalidades Craniofaciais , Displasia Septo-Óptica , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/patologia , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Displasia Septo-Óptica/genética , Displasia Septo-Óptica/patologia , Fatores de Tempo , Adulto Jovem
6.
Eur J Med Genet ; 58(5): 279-92, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25792522

RESUMO

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities, and subdivided in TRPS I, caused by mutations in TRPS1, and TRPS II, caused by a contiguous gene deletion affecting (amongst others) TRPS1 and EXT1. We performed a collaborative international study to delineate phenotype, natural history, variability, and genotype-phenotype correlations in more detail. We gathered information on 103 cytogenetically or molecularly confirmed affected individuals. TRPS I was present in 85 individuals (22 missense mutations, 62 other mutations), TRPS II in 14, and in 5 it remained uncertain whether TRPS1 was partially or completely deleted. Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella. The facial manifestations in patients with TRPS I and TRPS II do not show a significant difference. In the limbs the main findings are short hands and feet, hypermobility, and a tendency for isolated metacarpals and metatarsals to be shortened. Nails of fingers and toes are typically thin and dystrophic. The radiological hallmark are the cone-shaped epiphyses and in TRPS II multiple exostoses. Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally. Variability for all findings, also within a single family, can be marked. Morbidity mostly concerns joint problems, manifesting in increased or decreased mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age. Intellectual disability is uncommon in TRPS I and, if present, usually mild. In TRPS II intellectual disability is present in most but not all, and again typically mild to moderate in severity. Missense mutations are located exclusively in exon 6 and 7 of TRPS1. Other mutations are located anywhere in exons 4-7. Whole gene deletions are common but have variable breakpoints. Most of the phenotype in patients with TRPS II is explained by the deletion of TRPS1 and EXT1, but haploinsufficiency of RAD21 is also likely to contribute. Genotype-phenotype studies showed that mutations located in exon 6 may have somewhat more pronounced facial characteristics and more marked shortening of hands and feet compared to mutations located elsewhere in TRPS1, but numbers are too small to allow firm conclusions.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Síndrome de Langer-Giedion/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Lactente , Síndrome de Langer-Giedion/patologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Proteínas Repressoras , Adulto Jovem
7.
Eur J Med Genet ; 52(6): 379-80, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19679203

RESUMO

Genetic medicine is said to be entering another era. Recent technological developments such as high resolution array techniques and next-generation sequencing have dramatically increased the power of genetic testing. However, the function of the majority of genes remains unknown. The complex interactions underpinning gene expression in humans can be studied only in part by laboratory and animal studies, and will require studies in humans. Consequently, observational studies which systematically record human phenotype data are urgently needed to interpret molecular genetic variation.


Assuntos
Genética Médica , Expressão Gênica , Variação Genética , Humanos
8.
J Hum Genet ; 50(1): 21-25, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15690106

RESUMO

LEOPARD syndrome (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) is an autosomal dominant condition. The main clinical features include multiple lentigines, cardiovascular defects, and facial anomalies, some of which are shared with Noonan syndrome (NS). Recent reports have shown that LEOPARD syndrome can be caused by mutations in PTPN11, the gene in which mutations can produce NS. Here we report the findings of mutation screening and linkage analysis of PTPN11 in three families with LEOPARD syndrome. We identified a novel mutation in one family. The mutation (1529A>C) substitutes proline for glutamine at amino acid 510 (Gln510Pro). No variations in sequence were observed in the other two families, and negative LOD scores excluded linkage to the PTPN11 locus, showing that LEOPARD syndrome is genetically heterogeneous.


Assuntos
Síndrome LEOPARD/enzimologia , Síndrome LEOPARD/genética , Proteínas Tirosina Fosfatases/genética , Adolescente , Substituição de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , DNA/genética , Feminino , Ligação Genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Mutação , Síndrome de Noonan/enzimologia , Síndrome de Noonan/genética , Linhagem , Mutação Puntual , Proteína Tirosina Fosfatase não Receptora Tipo 11
9.
Hum Genet ; 111(4-5): 421-7, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12384786

RESUMO

CFC (cardiofaciocutaneous) syndrome (MIM 115150) has been considered by several authors to be a more severe expression of Noonan syndrome. Affected patients present with congenital heart defects, cutaneous abnormalities, Noonan-like facial features and severe psychomotor developmental delay. We have recently demonstrated that Noonan syndrome can be caused by missense mutations in PTPN11(MIM 176876), a gene that encodes the non-receptor protein tyrosine phosphatase SHP-2. In this report, we have evaluated the possible involvement of mutations in PTPN11 in CFC syndrome. A cohort of 28 CFC subjects rigorously assessed as having CFC based on OMIM diagnostic criteria was examined for mutations in the PTPN11 coding sequence by using DHPLC analysis. The results showed no abnormalities in the coding region of the PTPN11 gene in any CFC patient, nor any evidence of major deletions within the gene suggesting that mutations in other gene(s) are responsible for this syndrome.


Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Cardiopatias Congênitas/genética , Mutação de Sentido Incorreto , Anormalidades da Pele/genética , Sequência de Bases , Primers do DNA , Humanos , Síndrome de Noonan/genética , Síndrome
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