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1.
Am J Hum Genet ; 104(4): 758-766, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929739

RESUMO

By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.

2.
Eur J Med Genet ; 61(4): 213-218, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29191497

RESUMO

A higher diagnostic yield from new diagnostic techniques makes re-evaluation in patients with intellectual disability without a causal diagnosis valuable, and is currently only performed after new referral. Active recontacting might serve a larger group of patients. We aimed to evaluate parental perspectives regarding recontacting and its feasibility in clinical genetic practice. A recontacting pilot was performed in two cohorts of children with intellectual disability. In cohort A, parents were recontacted by phone and in cohort B by letter, to invite them for a re-evaluation due to the new technologies (array CGH and exome sequencing, respectively). Parental opinions, preferences and experiences with recontacting were assessed by a self-administered questionnaire, and the feasibility of this pilot was evaluated. 47 of 114 questionnaires were returned. In total, 87% of the parents believed that all parents should be recontacted in light of new insights, 17% experienced an (positive or negative) emotional reaction. In cohort A, approached by phone, 36% made a new appointment for re-evaluation, and in cohort B, approached by letter, 4% did. Most parents have positive opinions on recontacting. Recontacting might evoke emotional responses that may need attention. Recontacting is feasible but time-consuming and a large additional responsibility for clinical geneticists.


Assuntos
Dever de Recontatar , Aconselhamento Genético/psicologia , Testes Genéticos/normas , Deficiência Intelectual/genética , Pais/psicologia , Adolescente , Adulto , Atitude , Criança , Pré-Escolar , Feminino , Aconselhamento Genético/normas , Testes Genéticos/legislação & jurisprudência , Humanos , Masculino
3.
J Med Genet ; 53(8): 523-32, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27075013

RESUMO

BACKGROUND: AUTS2 syndrome is an 'intellectual disability (ID) syndrome' caused by genomic rearrangements, deletions, intragenic duplications or mutations disrupting AUTS2. So far, 50 patients with AUTS2 syndrome have been described, but clinical data are limited and almost all cases involved young children. METHODS: We present a detailed clinical description of 13 patients (including six adults) with AUTS2 syndrome who have a pathogenic mutation or deletion in AUTS2. All patients were systematically evaluated by the same clinical geneticist. RESULTS: All patients have borderline to severe ID/developmental delay, 83-100% have microcephaly and feeding difficulties. Congenital malformations are rare, but mild heart defects, contractures and genital malformations do occur. There are no major health issues in the adults; the oldest of whom is now 59 years of age. Behaviour is marked by it is a friendly outgoing social interaction. Specific features of autism (like obsessive behaviour) are seen frequently (83%), but classical autism was not diagnosed in any. A mild clinical phenotype is associated with a small in-frame 5' deletions, which are often inherited. Deletions and other mutations causing haploinsufficiency of the full-length AUTS2 transcript give a more severe phenotype and occur de novo. CONCLUSIONS: The 13 patients with AUTS2 syndrome with unique pathogenic deletions scattered around the AUTS2 locus confirm a phenotype-genotype correlation. Despite individual variations, AUTS2 syndrome emerges as a specific ID syndrome with microcephaly, feeding difficulties, dysmorphic features and a specific behavioural phenotype.


Assuntos
Deficiência Intelectual/genética , Transtornos Mentais/genética , Proteínas/genética , Adulto , Criança , Pré-Escolar , Éxons/genética , Feminino , Estudos de Associação Genética/métodos , Haploinsuficiência/genética , Humanos , Lactente , Masculino , Microcefalia/genética , Pessoa de Meia-Idade , Mutação/genética , Fenótipo , Deleção de Sequência/genética , Síndrome , Adulto Jovem
4.
Eur J Hum Genet ; 24(5): 652-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26306646

RESUMO

The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.


Assuntos
Anormalidades Múltiplas/diagnóstico , Deficiência Intelectual/diagnóstico , Proteínas Nucleares/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade
5.
Eur J Hum Genet ; 23(6): 803-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25205402

RESUMO

AUTS2 syndrome is characterized by low birth weight, feeding difficulties, intellectual disability, microcephaly and mild dysmorphic features. All affected individuals thus far were caused by chromosomal rearrangements, variants at the base pair level disrupting AUTS2 have not yet been described. Here we present the full clinical description of two affected men with intragenic AUTS2 variants (one two-base pair deletion in exon 7 and one deletion of exon 6). Both variants are de novo and are predicted to cause a frameshift of the full-length transcript but are unlikely to affect the shorter 3' transcript starting in exon 9. The similarities between the phenotypes of both men are striking and further support that AUTS2 syndrome is a single gene disorder.


Assuntos
Deleção de Genes , Deficiência Intelectual/genética , Microcefalia/genética , Polimorfismo Genético , Proteínas/genética , Éxons , Mutação da Fase de Leitura , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Fenótipo , Síndrome , Adulto Jovem
6.
Am J Hum Genet ; 92(2): 210-20, 2013 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-23332918

RESUMO

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3'AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.


Assuntos
Éxons/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Proteínas/química , Proteínas/genética , Deleção de Sequência/genética , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Sequência de Bases , Criança , Pré-Escolar , Facies , Feminino , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Fenótipo , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Supressão Genética , Síndrome , Adulto Jovem , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/química , Proteínas de Peixe-Zebra/genética
7.
J Med Genet ; 47(4): 271-5, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19752158

RESUMO

BACKGROUND: Intrachromosomal triplications are rare chromosomal rearrangements. In most triplication cases the phenotype is similar to, but more severe than observed in patients with a duplication of the same region. The Williams-Beuren syndrome (WBS) region on 7q11.23, is prone to chromosomal rearrangements. A common deletion causes the well-characterised Williams-Beuren syndrome. The reciprocal duplication has been described in 27 families only, and is associated with a variable phenotype, including speech delay with (mild) mental retardation, autism and mild dysmorphic features. As the duplication of the WBS region is sometimes found inunaffected parents, initially some doubts have been raised about the pathogenicity of the duplication. RESULTS AND METHODS: We here describe the first triplication of a large part of the WBS region, detected with array CGH and confirmed by MLPA and FISH. The phenotypic features include mental retardation, a severe expressive language delay, behavioural problems and dysmorphisms. CONCLUSION: These features are remarkably similar, but seem more severe, compared to features seen in duplication patients. Therefore, our findings support the idea that an amplification of the WBS region is a disease-causing event, although the penetrance might be incomplete.


Assuntos
Aberrações Cromossômicas , Rearranjo Gênico , Síndrome de Williams/genética , Sintomas Comportamentais/genética , Pré-Escolar , Cromossomos Humanos Par 7 , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/genética , Masculino , Fenótipo , Trissomia , Síndrome de Williams/diagnóstico , Síndrome de Williams/patologia
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