Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Mais filtros

Base de dados
Intervalo de ano de publicação
Artigo em Inglês | MEDLINE | ID: mdl-31479583


Sotos syndrome is an overgrowth-intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the published Sotos syndrome clinical descriptions are based on studies of children; the phenotype in adults with Sotos syndrome is not yet well described. Given that it is now 17 years since disruption of NSD1 was shown to cause Sotos syndrome, many of the children first reported are now adults. It is therefore timely to investigate the phenotype of 44 adults with Sotos syndrome and NSD1 pathogenic variants. We have shown that adults with Sotos syndrome display a wide spectrum of intellectual ability with functioning ranging from fully independent to fully dependent. Reproductive rates are low. In our cohort, median height in adult women is +1.9 SD and men +0.5 SD. There is a distinctive facial appearance in adults with a tall, square, prominent chin. Reassuringly, adults with Sotos syndrome are generally healthy with few new medical issues; however, lymphedema, poor dentition, hearing loss, contractures and tremor have developed in a small number of individuals.

Clin Genet ; 95(6): 693-703, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30859559


Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1-associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly-acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound-heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss-of-function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS-like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.-38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1-4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.

Am J Med Genet A ; 170(11): 2835-2846, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27667800


KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. We describe 32 KBG patients aged 2-47 years from 27 families ascertained via two pathways: targeted ANKRD11 sequencing (TS) in a group who had a clinical diagnosis of KBG and whole exome sequencing (ES) in a second group in whom the diagnosis was unknown. Speech delay and learning difficulties were almost universal and variable behavioral problems frequent. Macrodontia of permanent upper central incisors was seen in 85%. Other clinical features included short stature, conductive hearing loss, recurrent middle ear infection, palatal abnormalities, and feeding difficulties. We recognized a new feature of a wide anterior fontanelle with delayed closure in 22%. The subtle facial features of KBG syndrome were recognizable in half the patients. We identified 20 ANKRD11 mutations (18 novel: all truncating) confirmed by Sanger sequencing in 32 patients. Comparison of the two ascertainment groups demonstrated that facial/other typical features were more subtle in the ES group. There were no conclusive phenotype-genotype correlations. Our findings suggest that mutation of ANKRD11 is a common Mendelian cause of developmental delay. Affected patients may not show the characteristic KBG phenotype and the diagnosis is therefore easily missed. We propose updated diagnostic criteria/clinical recommendations for KBG syndrome and suggest that inclusion of ANKRD11 will increase the utility of gene panels designed to investigate developmental delay. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/genética , Deleção Cromossômica , Cromossomos Humanos Par 16 , Hibridização Genômica Comparativa , Facies , Feminino , Humanos , Masculino , Fenótipo , Proteínas Repressoras/genética
Mol Genet Genomic Med ; 4(3): 359-66, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27247962


BACKGROUND: Poikiloderma is defined as a chronic skin condition presenting with a combination of punctate atrophy, areas of depigmentation, hyperpigmentation and telangiectasia. In a variety of hereditary syndromes such as Rothmund-Thomson syndrome (RTS), Clericuzio-type poikiloderma with neutropenia (PN) and Dyskeratosis Congenita (DC), poikiloderma occurs as one of the main symptoms. Here, we report on genotype and phenotype data of a cohort of 44 index patients with RTS or related genodermatoses. METHODS: DNA samples from 43 patients were screened for variants in the 21 exons of the RECQL4 gene using PCR, SSCP-PAGE analysis and/or Sanger sequencing. Patients with only one or no detectable mutation in the RECQL4 gene were additionally tested for variants in the 8 exons of the USB1 (C16orf57) gene by Sanger sequencing. The effect of novel variants was evaluated by phylogenic studies, single-nucleotide polymorphism (SNP) databases and in silico analyses. RESULTS: We identified 23 different RECQL4 mutations including 10 novel and one homozygous novel USB1 (C16orf57) mutation in a patient with PN. Moreover, we describe 31 RECQL4 and 8 USB1 sequence variants, four of them being novel intronic RECQL4 sequence changes that may have some deleterious effects on splicing mechanisms and need further evaluation by transcript analyses. CONCLUSION: The current study contributes to the improvement of genetic diagnostic strategies and interpretation in RTS and PN that is relevant in order to assess the patients' cancer risk, to avoid continuous and inconclusive clinical evaluations and to clarify the recurrence risk in the families. Additionally, it shows that the phenotype of more than 50% of the patients with suspected Rothmund-Thomson disease may be due to mutations in other genes raising the need for further extended genetic analyses.

Am J Med Genet A ; 167A(12): 3153-60, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26333682


Submicroscopic deletions within chromosome 1q24q25 are associated with a syndromic phenotype of short stature, brachydactyly, learning difficulties, and facial dysmorphism. The critical region for the deletion phenotype has previously been narrowed to a 1.9 Mb segment containing 13 genes. We describe two further patients with 1q24 microdeletions and the skeletal phenotype, the first of whom has normal intellect, whereas the second has only mild learning impairment. The deletion in the first patient is very small and further narrows the critical interval for the striking skeletal aspects of this condition to a region containing only Dynamin 3 (DNM3) and two microRNAs that are harbored within intron 14 of this gene: miR199 and miR214. Mouse studies raise the possibility that these microRNAs may be implicated in the short stature and skeletal abnormalities of this microdeletion condition. The deletion in the second patient spans the previously reported critical region and indicates that the cognitive impairment may not always be as severe as previous reports suggest.

Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Dinamina III/genética , MicroRNAs/genética , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Animais , Doenças do Desenvolvimento Ósseo/patologia , Braquidactilia/genética , Braquidactilia/patologia , Hibridização Genômica Comparativa , Feminino , Humanos , Recém-Nascido , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Masculino , Camundongos , Fenótipo , Prognóstico , Síndrome , Gêmeos Monozigóticos/genética
Pediatr Cardiol ; 34(3): 771-3, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23052680


The case report describes a 9-year-old boy who presented with an acute cerebrovascular accident and was found to have cardiac tamponade caused by cardiac rhabdomyosarcoma. Symptoms of rhabdomyosarcoma can be indolent and nonspecific, even with metastatic disease. Echocardiography and cardiac magnetic resonance imaging are explored as adjuncts to diagnosis. The radiologic features that helped with the diagnosis of this rare condition are described.

Tamponamento Cardíaco/diagnóstico , Neoplasias Cardíacas/diagnóstico , Rabdomiossarcoma/diagnóstico , Acidente Vascular Cerebral/diagnóstico , Tamponamento Cardíaco/complicações , Tamponamento Cardíaco/cirurgia , Criança , Terapia Combinada , Ecocardiografia Doppler/métodos , Seguimentos , Gadolínio , Neoplasias Cardíacas/complicações , Neoplasias Cardíacas/cirurgia , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Doenças Raras , Rabdomiossarcoma/complicações , Rabdomiossarcoma/cirurgia , Medição de Risco , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/terapia