Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Genome Med ; 11(1): 12, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819258

RESUMO

BACKGROUND: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity). METHODS: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. RESULTS: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. CONCLUSIONS: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.


Assuntos
Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Mutação INDEL , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Síndrome de Smith-Magenis/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/patologia , Síndrome de Smith-Magenis/patologia , Fatores de Transcrição/metabolismo , Adulto Jovem
3.
Artigo em Inglês | MEDLINE | ID: mdl-30087776

RESUMO

Symptomatic pituitary adenomas occur with a prevalence of approximately 0.1% in the general population. It is estimated that 5% of pituitary adenomas occur in a familial setting, either in isolated or syndromic form. Recently, loss-of-function mutations in genes encoding succinate dehydrogenase subunits (SDHx) or MYC-associated factor X (MAX) have been found to predispose to pituitary adenomas in co-existence with paragangliomas or phaeochromocytomas. It is rare, however, for a familial SDHx mutation to manifest as an isolated pituitary adenoma. We present the case of a pituitary lactotroph adenoma in a patient with a heterozygous germline SDHB mutation, in the absence of concomitant neoplasms. Initially, the adenoma showed biochemical response but poor tumour shrinkage in response to cabergoline; therefore, transsphenoidal surgery was performed. Following initial clinical improvement, tumour recurrence was identified 15 months later. Interestingly, re-initiation of cabergoline proved successful and the lesion demonstrated both biochemical response and tumour shrinkage. Our patient's SDHB mutation was identified when we realised that her father had a metastatic paraganglioma, prompting genetic testing. Re-inspection of the histopathological report of the prolactinoma confirmed cells with vacuolated cytoplasm. This histological feature is suggestive of an SDHx mutation and should prompt further screening for mutations by immunohistochemistry and/or genetic testing. Surprisingly, immunohistochemistry of this pituitary adenoma demonstrated normal SDHB expression, despite loss of SDHB expression in the patient's father's paraganglioma. Learning points: Pituitary adenomas may be the presenting and/or sole feature of SDHB mutation-related disease. SDHx mutated pituitary adenomas may display clinically aggressive behaviour and demonstrate variable response to medical treatment.Histological evidence of intracytoplasmic vacuoles in a pituitary adenoma might suggest an SDH-deficient tumour and should prompt further screening for SDHx mutations.Immunohistochemistry may not always predict the presence of SDHx mutations.

4.
Am J Med Genet A ; 173(6): 1593-1600, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28440577

RESUMO

Isolated 7p22.3p22.2 deletions are rarely described with only two reports in the literature. Most other reported cases either involve a much larger region of the 7p arm or have an additional copy number variation. Here, we report five patients with overlapping microdeletions at 7p22.3p22.2. The patients presented with variable developmental delays, exhibiting relative weaknesses in expressive language skills and relative strengths in gross, and fine motor skills. The most consistent facial features seen in these patients included a broad nasal root, a prominent forehead a prominent glabella and arched eyebrows. Additional variable features amongst the patients included microcephaly, metopic ridging or craniosynostosis, cleft palate, cardiac defects, and mild hypotonia. Although the patients' deletions varied in size, there was a 0.47 Mb region of overlap which contained 7 OMIM genes: EIP3B, CHST12, LFNG, BRAT1, TTYH3, AMZ1, and GNA12. We propose that monosomy of this region represents a novel microdeletion syndrome. We recommend that individuals with 7p22.3p22.2 deletions should receive a developmental assessment and a thorough cardiac exam, with consideration of an echocardiogram, as part of their initial evaluation.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Deficiências do Desenvolvimento/genética , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Lactente , Masculino , Monossomia
5.
Am J Hum Genet ; 100(4): 650-658, 2017 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-28343630

RESUMO

Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.


Assuntos
Éxons , Deficiência Intelectual/genética , Mutação , Proteína Fosfatase 2C/genética , Adolescente , Ciclo Celular , Criança , Pré-Escolar , Humanos , Deficiência Intelectual/patologia , Adulto Jovem
6.
Hum Mutat ; 35(11): 1295-300, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25196122

RESUMO

We report de novo occurrence of the 7p11.2 folate-sensitive fragile site FRA7A in a male with an autistic spectrum disorder (ASD) due to a CGG-repeat expansion mutation (∼450 repeats) in a 5' intron of ZNF713. This expanded allele showed hypermethylation of the adjacent CpG island with reduced ZNF713 expression observed in a proband-derived lymphoblastoid cell line (LCL). His unaffected mother carried an unmethylated premutation (85 repeats). This CGG-repeat showed length polymorphism in control samples (five to 22 repeats). In a second unrelated family, three siblings with ASD and their unaffected father were found to carry FRA7A premutations, which were partially or mosaically methylated. In one of the affected siblings, mitotic instability of the premutation was observed. ZNF713 expression in LCLs in this family was increased in three of these four premutation carriers. A firm link cannot yet be established between ASD and the repeat expansion mutation but plausible pathogenic mechanisms are discussed.


Assuntos
Transtorno Autístico/genética , Sítios Frágeis do Cromossomo , Proteínas de Ligação a DNA/genética , Estudos de Associação Genética , Expansão das Repetições de Trinucleotídeos , Adulto , Alelos , Transtorno Autístico/diagnóstico , Criança , Cromossomos Humanos Par 7 , Ilhas de CpG , Metilação de DNA , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Linhagem , Análise de Sequência de DNA , Fatores de Transcrição/genética
8.
Fam Cancer ; 7(3): 259-64, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18246448

RESUMO

Some studies have found a deficiency of male, younger and more socially deprived individuals amongst referrals to and/or attendees at cancer genetics clinics. We investigated this inequality of use of genetics services from data on 4,178 Scottish patients with a family history of breast and/or ovarian cancer (BOC) or colorectal cancer (CRC) referred from 2000--2006. Some 98% BOC and 60% CRC referrals were female. Median age of female referrals was greater in the CRC than the BOC group (45.3 vs. 38.7 years, P < 0.001). Both groups of referrals were less socially deprived than the general population (P < 0.001) and the CRC less deprived than the BOC group (P < 0.001). Some 88% patients attended the first appointment offered. Attendance was greater in the CRC group (P < 0.001) and in older patients (P < 0.001) and in the BOC group was highly significantly lower in more socially deprived patients (P < 0.001). Male relatives may feel counselling is less relevant and relatives of both sexes may delay counselling until approaching the age of onset of cancer in a relative. We suggest that medical professionals and the general public may have more knowledge about the genetics of BOC than of CRC. Thus relatives in CRC families seeking counselling are likely to be those with access to more information. The lower attendance amongst more deprived relatives in BOC families may result from poor understanding of the reason for referral. These findings confirm the need to provide male, younger and more socially deprived relatives with more helpful information on cancer genetics.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Aconselhamento Genético/estatística & dados numéricos , Acesso aos Serviços de Saúde , Necessidades e Demandas de Serviços de Saúde , Disparidades nos Níveis de Saúde , Neoplasias Ovarianas/genética , Aceitação pelo Paciente de Cuidados de Saúde , Adulto , Feminino , Doenças Genéticas Inatas , Testes Genéticos , Humanos , Renda , Modelos Logísticos , Masculino , Anamnese , Pessoa de Meia-Idade , Pobreza , Fatores de Risco , Escócia , Fatores Socioeconômicos
9.
Eur J Hum Genet ; 16(8): 906-12, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18285832

RESUMO

We investigated the uptake of genetic testing by 54 families in South East Scotland with a BRCA1/2 mutation. At a median of 37 months since identification of the mutation, the overall rate of uptake of testing in 269 eligible family members was 32%. First-degree relatives were significantly (P<0.05) less likely to be referred for genetic counselling in more, compared to less, socioeconomically deprived families (46 versus 68%). Among relatives who attended for genetic counselling, females were more likely to be tested than males (76 versus 53%; P<0.05) and relatives with children more than those without children (82 versus 53%; P<0.001). Tested relatives were older than relatives who did not undergo testing (mean 41.9 versus 36.8 years, P<0.05) but did not differ in degree of relationship to the index case or in socioeconomic deprivation. Our results confirm the findings from other studies of substantially lower rates of uptake of genetic testing for BRCA1/2 mutations than anticipated in earlier predictions. Relatives in more socioeconomically deprived families were less likely to be referred for genetic counselling, which is a matter of concern. This may be partly the result of a lack of understanding of the testing process. Cascading currently does not work in breast cancer families and further work is required to investigate intrafamilial communication patterns, testing behaviour and counselling strategies.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/psicologia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Adulto , Família , Feminino , Aconselhamento Genético , Testes Genéticos/psicologia , Testes Genéticos/estatística & dados numéricos , Humanos , Masculino , Escócia
10.
Am J Med Genet A ; 140(23): 2625-30, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16906569

RESUMO

We report on the occurrence of discrete patches of unusually long pigmented hair on the skin of three patients with Gorlin syndrome from two unrelated families with confirmed heterozygous mutations in the Patched (PTCH) gene. The PTCH protein is a negative regulator of Hedgehog signaling, and the Sonic Hedgehog (SHH)-PTCH pathway is known to play an important role in the formation and cycling of the hair follicle. We believe that the patches represent a genuine physical sign associated with Gorlin syndrome, and discuss molecular mechanisms by which they might arise.


Assuntos
Síndrome do Nevo Basocelular/patologia , Cabelo/crescimento & desenvolvimento , Mutação , Receptores de Superfície Celular/genética , Síndrome do Nevo Basocelular/genética , Pré-Escolar , Feminino , Folículo Piloso/crescimento & desenvolvimento , Humanos , Hipertricose/genética , Hipertricose/patologia , Lactente , Masculino , Modelos Biológicos , Receptores Patched , Receptor Patched-1
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA