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1.
Hum Mutat ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31692161

RESUMO

Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES-based methods and a more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.

3.
Wellcome Open Res ; 3: 46, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29900417

RESUMO

Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novoDNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS.

4.
J Med Genet ; 54(9): 613-623, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28735298

RESUMO

BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far. METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting. RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability. CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.


Assuntos
Fatores de Transcrição Forkhead/genética , Deficiência Intelectual/genética , Proteínas Repressoras/genética , Transtorno do Espectro Autista/genética , Face/anormalidades , Feminino , Fatores de Transcrição Forkhead/química , Fatores de Transcrição Forkhead/metabolismo , Humanos , Transtornos da Linguagem/genética , Masculino , Transtornos das Habilidades Motoras/genética , Mutação , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Estabilidade Proteica , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Síndrome , Transcrição Genética
5.
J Med Genet ; 54(12): 825-829, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28592524

RESUMO

BACKGROUND: Congenital heart disease (CHD) is a common birth defect affecting approximately 1% of newborns. Great progress has been made in elucidating the genetic aetiology of CHD with advances in genomic technology, which we leveraged in recovering a new pathway affecting heart development in humans previously known to affect heart development in an animal model. METHODS: Four hundred and sixteen individuals from Thailand and the USA diagnosed with CHD and/or congenital diaphragmatic hernia were evaluated with chromosomal microarray and whole exome sequencing. The DECIPHER Consortium and medical literature were searched for additional patients. Murine hearts from ENU-induced mouse mutants and transgenic mice were evaluated using both episcopic confocal histopathology and troponin I stained sections. RESULTS: Loss of function ROBO1 variants were identified in three families; each proband had a ventricular septal defect, and one proband had tetralogy of Fallot. Additionally, a microdeletion in an individual with CHD was found in the medical literature. Mouse models showed perturbation of the Slit-Robo signalling pathway, causing septation and outflow tract defects and craniofacial anomalies. Two probands had variable facial features consistent with the mouse model. CONCLUSION: Our findings identify Slit-Robo as a significant pathway in human heart development and CHD.


Assuntos
Defeitos dos Septos Cardíacos/diagnóstico , Defeitos dos Septos Cardíacos/genética , Mutação com Perda de Função , Proteínas do Tecido Nervoso/genética , Fenótipo , Receptores Imunológicos/genética , Tetralogia de Fallot/diagnóstico , Tetralogia de Fallot/genética , Animais , Criança , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Camundongos , Polimorfismo de Nucleotídeo Único
6.
N Z Med J ; 129(1445): 67-74, 2016 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-27857240

RESUMO

AIM: To investigate regional variations in the detection of sudden death syndromes across New Zealand by assessing registrations in the national Cardiac Inherited Diseases Registry New Zealand (CIDRNZ). METHODS: The CIDRNZ has been a national entity since 2009, with a hub in Auckland and locally funded regional coordinators (Midland, Central) linked with multidisciplinary cardiac genetic teams. Registration is consent-based and voluntary, and involves the collection of clinical/genetic information and permits genetic testing and research. Registry data were extracted from the CIDRNZ in October 2015 and results are expressed as registrations per 100,000 people by district health board area. RESULTS: The CIDRNZ has 1,940 registrants from 712 families, 46% of whom are definitely or probably affected by cardiac inherited disease. There are clear regional differences in registration frequencies between regions and between the North and South Islands, both for overall registrations (56/100,000 and 14/100,000, respectively; p<0.001) and for long QT syndrome registrations (15/100,000 and 6/100,000, respectively; p<0.001). Regions with local coordinators have the highest number of registrations. CONCLUSION: The detection of sudden death syndromes in New Zealand through a cardiac genetic registry is possible but much work is needed to improve regional variation in the detection/reporting of these conditions across the country.


Assuntos
Morte Súbita Cardíaca/epidemiologia , Programas de Rastreamento/métodos , Sistema de Registros/estatística & dados numéricos , Distribuição por Idade , Causas de Morte , Atestado de Óbito , Morte Súbita Cardíaca/prevenção & controle , Feminino , Acesso aos Serviços de Saúde/estatística & dados numéricos , Humanos , Masculino , Nova Zelândia/epidemiologia
7.
Neuromuscul Disord ; 26(11): 744-748, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27751653

RESUMO

Autosomal dominantly inherited mutations of BICD2 are associated with congenital-onset spinal muscular atrophy characterised by lower limb predominance. A few cases have also showed upper motor neuron pathology, including presenting with features resembling hereditary spastic paraplegia. The age-of-onset for the published families is usually at birth but also included cases with childhood- and adult-onset disease. In this report we described two isolated probands that presented in utero with features associated with reduced fetal movements. Both cases were diagnosed at birth with arthrogryposis multiplex congenita (AMC) and hypotonia. Other variable features included congenital fractures, hip dislocation, micrognathia, respiratory insufficiency, microcephaly and bilateral perisylvian polymicrogyria. Patient 1 is 4 years of age and stable, but shows significant motor developmental delay and delayed speech. Patient 2 passed away at 7 weeks of age. Through next generation sequencing we identified the same missense substitution in BICD2 (p.Arg694Cys) in both probands. Sanger sequencing showed that in both cases the mutation arose de novo. The in utero onset in both cases suggests that the p.Arg694Cys substitution may have a more deleterious effect on BICD2 function than previously described mutations. Our results broaden the phenotypes associated with BICD2 mutations to include AMC and cortical malformations and therefore to a similar phenotypic spectrum to that associated with its binding partner DYNC1H1.


Assuntos
Anormalidades Múltiplas/genética , Artrogripose/genética , Deficiência Intelectual/genética , Malformações do Desenvolvimento Cortical/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/terapia , Artrogripose/diagnóstico por imagem , Artrogripose/terapia , Pré-Escolar , Evolução Fatal , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/terapia , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/terapia , Fenótipo
8.
Am J Med Genet A ; 164A(12): 3027-34, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25258245

RESUMO

Distal limb contractures (DLC) represent a heterogeneous clinical and genetic condition. Overall, 20-25% of the DLC are caused by mutations in genes encoding the muscle contractile apparatus. Large interstitial deletions of the 3p have already been diagnosed by standard chromosomal analysis, but not associated with a specific phenotype. We report on four patients with syndromic DLC presenting with a de novo 3p14.1p13 microdeletion. The clinical features associated multiple contractures, feeding problems, developmental delay, and intellectual disability. Facial dysmorphism was constant with low-set posteriorly rotated ears and blepharophimosis. Review of previously reported cases with a precise mapping of the deletions, documented a 250 kb smallest region of overlap (SRO) necessary for DLC. This region contained one gene, EIF4E3, the first three exons of the FOXP1 gene, and an intronic enhancer of FOXP1 named hs1149. Sanger sequencing and locus quantification of hs1149, EIF4E3, and FOXP1 in a cohort of 11 French patients affected by DLC appeared normal. In conclusion, we delineate a new microdeletion syndrome involving the 3p14.1p13 locus and associated with DLC and severe developmental delay.


Assuntos
Artrogripose/epidemiologia , Aberrações Cromossômicas , Cromossomos Humanos Par 3/genética , Contratura/epidemiologia , Contratura/genética , Extremidades/patologia , Animais , Proteínas de Transporte/genética , Hibridização Genômica Comparativa , Contratura/patologia , Feminino , Fatores de Transcrição Forkhead/genética , França/epidemiologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Proteínas Repressoras/genética , Síndrome
9.
Pediatrics ; 129(3): e817-20, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22311990

RESUMO

Resistance to thyroid hormone is an uncommon problem, which has rarely been associated with thyroid dysgenesis. We report a case with both thyroid gland ectopy and resistance to thyroid hormone and, thus, a reduced capacity to produce and respond to thyroid hormone. The patient presented at 2 years of age with developmental delay, dysmorphic features, and elevation in both thyroxine and thyrotropin. We document her response to therapy with thyroxine, with particular regard to her growth and development. Persistent elevation of thyrotropin is commonly recognized during treatment of congenital hypothyroidism. Resistance to thyroid hormone may be an important additional diagnosis to consider in cases where thyrotropin remains persistently elevated.


Assuntos
Coristoma/diagnóstico , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/tratamento farmacológico , Resistência a Medicamentos , Glândula Tireoide , Tri-Iodotironina/uso terapêutico , Estatura/efeitos dos fármacos , Desenvolvimento Infantil/efeitos dos fármacos , Pré-Escolar , Hipotireoidismo Congênito/complicações , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/etiologia , Feminino , Seguimentos , Humanos , Medição de Risco , Índice de Gravidade de Doença , Testes de Função Tireóidea , Resultado do Tratamento
10.
Heart Rhythm ; 8(3): 412-9, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21070882

RESUMO

BACKGROUND: Retrospective investigation of sudden unexplained death in the young (SUDY) reveals that a high proportion is due to inherited heart disease. OBJECTIVE: The purpose of this study was to ascertain the diagnostic value of postmortem long QT (LQT) genetic analysis in a prospective study of SUDY victims 1-40 years old. METHODS: Denaturing high-performance liquid chromatography or direct sequencing of LQT genes 1, 2, 3, 5, and 6 was performed, in a National New Zealand protocol, in SUDY victims aged 1-40 years. RESULTS: Over 26 months (2006-2008), DNA was stored at autopsy from 52 victims of sudden unexpected death. Further testing revealed a diagnosis in 19 cases (poisoning 4, dilated cardiomyopathy 3, myocarditis 3, other 9). The remaining 33 cases underwent genetic testing (age at death 18 months-40 years, median 25 years). Eighteen (55%) died during sleep or at rest, and 7 (21%) died during light activity. Rare missense variants in LQT genes were found in 5 (15%) cases (confidence interval 3%-27%): T96R in KCNQ1 (11-year-old male), P968L in KCNH2 (32-year-old female), P2006A in SCN5A (34-year-old female), and R67H and R98W in KCNE1 (17- and 38-year-old females, respectively). Evidence of pathogenicity was provided by in vitro evidence (T96R), family phenotype-genotype co-segregation (R98W, P2006A), and/or previous reports (R67H, P968L, P2006A, R98W). Family cardiac investigation was possible in 23 (70%) families and revealed probable cause of death for 5 (15%) other victims (confidence interval 3%-27%). CONCLUSION: Most community SUDY occurs at rest or during light activity. A diagnostic rate of 15% supports the transition of LQT genetic autopsy, combined with family investigation, into routine medical practice.


Assuntos
Morte Súbita Cardíaca/epidemiologia , Síndrome do QT Longo/genética , Canais de Potássio/genética , Canais de Sódio/genética , Adolescente , Adulto , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Feminino , Testes Genéticos , Humanos , Lactente , Canal de Potássio KCNQ1/genética , Síndrome do QT Longo/epidemiologia , Masculino , Mutação de Sentido Incorreto , Canal de Sódio Disparado por Voltagem NAV1.5 , Nova Zelândia/epidemiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Estudos Prospectivos , Estudos Soroepidemiológicos , Adulto Jovem
11.
Pediatr Blood Cancer ; 55(4): 722-4, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20806366

RESUMO

Börjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked mental retardation syndrome that is caused by germline mutations in PHF6. We describe a 9-year-old male with BFLS, who developed T-cell acute lymphoblastic leukemia (T-ALL). The PHF6 gene is located on the X chromosome and encodes a protein with two PHD-type zinc finger domains and four nuclear localization sequences. Previously, overexpression of Phf6 was observed in murine T-cell lymphomas. Our observation indicates that BFLS may represent a cancer predisposition syndrome and that mutations of PHF6 contribute to T-ALL.


Assuntos
Proteínas de Transporte/genética , Retardo Mental Ligado ao Cromossomo X/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Criança , Humanos , Masculino
12.
Allergy Asthma Clin Immunol ; 6(1): 12, 2010 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-20529312

RESUMO

Primary immune deficiency disorders (PIDs) are a group of diseases associated with a genetic predisposition to recurrent infections, malignancy, autoimmunity and allergy. The molecular basis of many of these disorders has been identified in the last two decades. Most are inherited as single gene defects. Identifying the underlying genetic defect plays a critical role in patient management including diagnosis, family studies, prognostic information, prenatal diagnosis and is useful in defining new diseases. In this review we outline the clinical utility of molecular testing for these disorders using clinical cases referred to Auckland Hospital. It is written from the perspective of a laboratory offering a wide range of tests for a small developed country.

13.
Clin Dysmorphol ; 15(1): 1-8, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16317299

RESUMO

We report a 30-month-old female with intrauterine growth retardation, postnatal failure to thrive, pancytopoenia and myelodysplasia with monosomy 7 in the marrow. The child succumbed to overwhelming sepsis, following a bone marrow transplant to facilitate chemotherapy for metastatic hepatoblastoma--a tumour that has not been previously reported in myelodysplasia syndromes. Cytogenetic, molecular and microarray analysis of peripheral blood, skin fibroblasts and bone marrow revealed unusual results, suggestive of somatic chromosome instability. A normal peripheral blood karyotype was documented in infancy. Monosomy 7 was found in the bone marrow. Molecular (microsatellite marker) results for a later peripheral blood specimen were suggestive of partial maternal isodisomy 7q, and this was supported by microarray data on single-nucleotide polymorphisms. Microarray data on gene copy number, collected for the same blood specimen, indicated cryptic mosaicism for the monosomy 7 cell line, with the monosomic line lacking the paternal copy. In fibroblasts, cytogenetic data showed mosaic partial trisomy for distal 7p.


Assuntos
Cromossomos Humanos Par 7/genética , Hepatoblastoma/genética , Monossomia/genética , Mosaicismo , Defeitos do Tubo Neural/genética , Transplante de Medula Óssea , Pré-Escolar , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Hepatoblastoma/patologia , Hepatoblastoma/terapia , Humanos , Monossomia/patologia , Defeitos do Tubo Neural/patologia , Defeitos do Tubo Neural/terapia
15.
J Paediatr Child Health ; 41(7): 380-1, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16014147

RESUMO

We present two neonates with nasal obstruction because of anterior choanal stenosis (congenital nasal pyriform aperture stenosis). An associated single maxillary central incisor was also shown on computed tomography imaging in the neonatal period. These midline anomalies are recognized minimal manifestations (microforms) of holoprosencephaly. We describe their neonatal investigation, multidisciplinary management and clinical course.


Assuntos
Incisivo/anormalidades , Doenças do Recém-Nascido , Seio Maxilar/anormalidades , Obstrução Nasal/congênito , Feminino , Holoprosencefalia , Humanos , Recém-Nascido , Masculino , New South Wales
16.
Hum Mutat ; 25(6): 593-4, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15880723

RESUMO

Pseudoachondroplasia (PSACH) and some forms of multiple epiphyseal dysplasia (MED) result from mutations in the gene encoding cartilage oligomeric matrix protein (COMP). COMP is a large pentameric glycoprotein found predominantly in the extracellular matrix of cartilage, tendon, and ligament. As a modular protein, it is composed of a coiled-coil domain, four type II (T2) repeats, eight type III (T3) repeats, and a large globular C-terminal domain (CTD). The majority (>85%) of COMP mutations causing PSACH or MED are found in the exons encoding the T3 repeats, and the disease mechanism has been characterised in detail. Much less is known about disease-causing mutations in the CTD; in 10 years only seven mutations have been identified. In this study, we describe eight novel and two recurrent mutations that we have recently identified in patients with PSACH or MED. Interestingly, these mutations result in a spectrum of disease, ranging from mild MED to severe PSACH. Mapping of all known COMP CTD mutations on a three-dimensional model of the C-terminal domain shows that the CTD mutations cluster in two distinct regions. These regions are probably important in stabilising the T3-CTD structure and mediating intra- or intermolecular interactions.


Assuntos
Acondroplasia/genética , Proteínas da Matriz Extracelular/química , Proteínas da Matriz Extracelular/genética , Glicoproteínas/química , Glicoproteínas/genética , Mutação/genética , Fenótipo , Acondroplasia/diagnóstico por imagem , Proteína de Matriz Oligomérica de Cartilagem , Criança , Pré-Escolar , Análise Mutacional de DNA , Éxons/genética , Humanos , Proteínas Matrilinas , Modelos Moleculares , Radiografia
17.
Am J Med Genet A ; 132A(4): 425-30, 2005 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-15633179

RESUMO

We report on three male infants with de novo terminal deletions of chromosome 9q34.3. The clinical features are compared to the nine cases described in the literature. Case 1 and 3 were ascertained following the use of subtelomeric FISH to screen for a chromosomal anomaly, case 2 was confirmed by FISH probe following detection of a 9q deletion on standard karyotyping. Deletions in this region result in severe developmental delay, a distinct facial phenotype, cardiac anomalies, obesity, and respiratory failure, which may result in premature death. The delineation of the 9q deletion phenotype will aid diagnosis and genetic counseling as subtelomere FISH screening becomes more widely available.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 9/genética , Telômero/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Bandeamento Cromossômico , Deficiências do Desenvolvimento/patologia , Face/anormalidades , Evolução Fatal , Cardiopatias Congênitas/patologia , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , Insuficiência Respiratória/patologia
18.
Clin Dysmorphol ; 12(3): 179-81, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-14564156

RESUMO

We describe the phenotypic features in a newborn infant with an unbalanced translocation 46,XY, der(22) inv(4) (p14p16.1) t(4;22) (p15.1;q13.31)pat. The phenotype was consistent with partial trisomy 4p syndrome. Severe bilateral hydronephrosis was diagnosed at a 31 week prenatal ultrasound scan. Both the patient phenotype and the partial trisomy are unusual, the latter due to the complex nature of the chromosomal rearrangement.


Assuntos
Cromossomos Humanos Par 4 , Doenças Fetais/genética , Hidronefrose/genética , Trissomia , Feminino , Doenças Fetais/diagnóstico por imagem , Humanos , Hidronefrose/congênito , Hidronefrose/diagnóstico por imagem , Recém-Nascido , Fenótipo , Índice de Gravidade de Doença , Ultrassonografia Pré-Natal
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