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1.
Am J Hum Genet ; 104(2): 319-330, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639322

RESUMO

ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.

2.
BMC Med Genet ; 19(1): 90, 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29843636

RESUMO

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by the development of hamartomas in multiple organs, including the brain, heart, skin, kidney, lung and retina. A diagnosis of TSC is established with a recently revised clinical/radiological set of criteria and/or a causative mutation in TSC1 or TSC2 gene. CASE PRESENTATION: We report a Chinese TSC family with two siblings presenting with multiple hypomelanotic macules, cardiac rhabdomyomas and cortical tubers associated with a small subependymal nodule. The older child had seizures. A novel heterozygous missense variant in the TSC2 gene (c.899G > T, p.G300 V) was identified and shown to be inherited from their father as well as paternal grandfather, both of whom presented with variable TSC-associated signs and symptoms. CONCLUSION: We identified a novel heterozygous TSC2 variant c.899G > T as the causative mutation in a Chinese family with TSC, resulting in wide intrafamilial phenotypic variability. Our study illustrates the importance of clinical evaluation and genetic testing for family members of the patient affected with TSC.

3.
Genet Med ; 20(9): 1061-1068, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29215649

RESUMO

PURPOSE: The craniosynostoses are characterized by premature fusion of one or more cranial sutures. The relative contribution of previously reported genes to craniosynostosis in large cohorts is unclear. Here we report on the use of a massively parallel sequencing panel in individuals with craniosynostosis without a prior molecular diagnosis. METHODS: A 20-gene panel was designed based on the genes' association with craniosynostosis, and clinically validated through retrospective testing of an Australian and New Zealand cohort of 233 individuals with craniosynostosis in whom previous testing had not identified a causative variant within FGFR1-3 hot-spot regions or the TWIST1 gene. An additional 76 individuals were tested prospectively. RESULTS: Pathogenic or likely pathogenic variants in non-FGFR genes were identified in 43 individuals, with diagnostic yields of 14% and 15% in retrospective and prospective cohorts, respectively. Variants were identified most frequently in TCF12 (N = 22) and EFNB1 (N = 8), typically in individuals with nonsyndromic coronal craniosynostosis or TWIST1-negative clinically suspected Saethre-Chotzen syndrome. Clinically significant variants were also identified in ALX4, EFNA4, ERF, and FGF10. CONCLUSION: These findings support the clinical utility of a massively parallel sequencing panel for craniosynostosis. TCF12 and EFNB1 should be included in genetic testing for nonsyndromic coronal craniosynostosis or clinically suspected Saethre-Chotzen syndrome.

4.
Am J Med Genet A ; 176(1): 181-186, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29159987

RESUMO

We report two unrelated patients with Pierre Robin sequence (PRS) and a strikingly similar combination of associated features. Whole exome sequencing was performed for both patients. No single gene containing likely pathogenic point mutations in both patients could be identified, but the finding of an essential splice site mutation in mediator complex subunit 13 like (MED13L) in one patient prompted the investigation of copy number variants in MED13L in the other, leading to the identification of an intragenic deletion. Disruption of MED13L, encoding a component of the Mediator complex, is increasingly recognized as the cause of an intellectual disability syndrome with associated facial dysmorphism. Our findings suggest that MED13L-related disorders are a possible differential diagnosis for syndromic PRS.


Assuntos
Mutação com Perda de Função , Complexo Mediador/genética , Síndrome de Pierre Robin/diagnóstico , Síndrome de Pierre Robin/genética , Encéfalo/anormalidades , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Lactente , Imagem por Ressonância Magnética/métodos , Masculino , Fenótipo , Análise de Sequência de DNA
5.
Prenat Diagn ; 37(10): 975-982, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28685502

RESUMO

OBJECTIVE: The aim of this study was to (1) examine the psychological impact of non-invasive prenatal testing (NIPT) in women with a high-risk (≥1 : 300) and low-risk (≤1 : 301) result on combined first trimester screening (cFTS) and (2) to examine factors influencing anxiety and decision-making in both risk populations. METHOD: Questionnaires and structured interviews were administered to low (n = 50) and high (n = 63) risk women at the time of NIPT blood draw (point A) and again at least 1 week after receiving their NIPT result (point B). Anxiety levels were measured at these two time points using the State-Trait Anxiety Inventory. RESULTS: Both high-risk and low-risk cFTS groups demonstrated similar intrinsic (trait) anxiety levels (36 ± 10 vs 35 ± 10; p = 0.70). High-risk women had significantly higher levels of state anxiety at point A than low-risk women (42 ± 11 vs 36 ± 11; p < 0.01). Both groups had a statistically significant reduction (p < 0.01), to similar final levels of state anxiety at point B (30 ± 11 vs 29 ± 8; p = 0.61). CONCLUSION: Women receiving a high-risk result on cFTS have higher levels of state anxiety than their low-risk counterparts. Following a low-risk NIPT result, the anxiety levels in both populations are reduced to similar levels. © 2017 John Wiley & Sons, Ltd.


Assuntos
Aneuploidia , Ansiedade/epidemiologia , Diagnóstico Pré-Natal/métodos , Diagnóstico Pré-Natal/psicologia , Adulto , Ansiedade/prevenção & controle , Ansiedade/psicologia , DNA/sangue , Tomada de Decisões , Feminino , Idade Gestacional , Humanos , New South Wales/epidemiologia , Medição da Translucência Nucal , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Complicações na Gravidez/psicologia , Primeiro Trimestre da Gravidez , Fatores de Risco , Inquéritos e Questionários
6.
JIMD Rep ; 34: 1-9, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27469131

RESUMO

BACKGROUND: Asparagine Synthetase Deficiency (ASNSD; OMIM #615574) is a newly described rare autosomal recessive neurometabolic disorder, characterised by congenital microcephaly, severe psychomotor delay, encephalopathy and progressive cerebral atrophy. To date, seven families and seven missense mutations in the ASNSD disease causing gene, ASNS, have been published. METHODS: We report two further affected infant sisters from a consanguineous Indian family, who in addition to the previously described features had diaphragmatic eventration. Both girls died within the first 6 months of life. Whole exome sequencing (WES) was performed for both sisters to identify the pathogenic mutation. The clinical and biochemical parameters of our patient are compared to previous reports. RESULTS: WES demonstrated a homozygous novel missense ASNS mutation, c.1019G > A, resulting in substitution of the highly conserved arginine residue by histidine (R340H). CONCLUSION: This report expands the phenotypic and mutation spectrum of ASNSD, which should be considered in neonates with congenital microcephaly, seizures and profound neurodevelopmental delay. The presence of diaphragmatic eventration suggests extracranial involvement of the central nervous system in a disorder that was previously thought to exclusively affect the brain. Like all previously reported patients, these cases were diagnosed with WES, highlighting the clinical utility of next generation sequencing in the diagnosis of rare, difficult to recognise disorders.

7.
Am J Hum Genet ; 98(4): 772-81, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27040692

RESUMO

Infantile encephalopathies are a group of clinically and biologically heterogeneous disorders for which the genetic basis remains largely unknown. Here, we report a syndromic neonatal encephalopathy characterized by profound developmental disability, severe hypotonia, seizures, diminished respiratory drive requiring mechanical ventilation, brain atrophy, dysgenesis of the corpus callosum, cerebellar vermis hypoplasia, and facial dysmorphism. Biallelic inactivating mutations in TBCK (TBC1-domain-containing kinase) were independently identified by whole-exome sequencing as the cause of this condition in four unrelated families. Matching these families was facilitated by the sharing of phenotypic profiles and WES data in a recently released web-based tool (Geno2MP) that links phenotypic information to rare variants in families with Mendelian traits. TBCK is a putative GTPase-activating protein (GAP) for small GTPases of the Rab family and has been shown to control cell growth and proliferation, actin-cytoskeleton dynamics, and mTOR signaling. Two of the three mutations (c.376C>T [p.Arg126(∗)] and c.1363A>T [p.Lys455(∗)]) are predicted to truncate the protein, and loss of the major TBCK isoform was confirmed in primary fibroblasts from one affected individual. The third mutation, c.1532G>A (p.Arg511His), alters a conserved residue within the TBC1 domain. Structural analysis implicated Arg511 as a required residue for Rab-GAP function, and in silico homology modeling predicted impaired GAP function in the corresponding mutant. These results suggest that loss of Rab-GAP activity is the underlying mechanism of disease. In contrast to other disorders caused by dysregulated mTOR signaling associated with focal or global brain overgrowth, impaired TBCK function results in progressive loss of brain volume.


Assuntos
Encefalopatias/genética , Proteínas Ativadoras de GTPase/genética , Proteínas Serina-Treonina Quinases/genética , Adolescente , Alelos , Sequência de Aminoácidos , Encefalopatias/diagnóstico , Criança , Pré-Escolar , Corpo Caloso/patologia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Conformação Proteica , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
10.
J Pediatr ; 164(5): 1195-200, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24518170

RESUMO

OBJECTIVES: To evaluate the efficacy and side effects of oral mammalian target of rapamycin (mTOR) inhibitors in children and adolescents with tuberous sclerosis complex (TSC) and intractable epilepsy or subependymal giant cell astrocytoma (SEGA). STUDY DESIGN: Single-center series of 13 children and adolescents with TSC who received sirolimus or everolimus (mTOR inhibitors). The anticonvulsant response was evaluated in 7 patients with TSC and refractory seizures. Six patients with SEGAs were treated with either sirolimus or everolimus for nonsurgical management. SEGA volumes were assessed longitudinally using 1.5-T magnetic resonance imaging. RESULTS: Of the intractable seizure group (7 patients), 1 patient had >90% reduction, 4 had 50%-90% reduction, and 2 had <50% reduction. Three reported subjective improvements in learning. By 12 months of treatment, there were statistically significant reductions in the SEGA volumes in 4 patients who received mTOR inhibitors (P < .04). The mean SEGA volume after 6 months of treatment was 2.18 cm(3), which represents 33% reduction in the mean baseline volume of 3.26 cm(3). The mTOR inhibitors were well tolerated. Adverse effects include dyslipidaemia (3 of 13), gingivitis (1 of 13), anorexia (1 of 13), and mild gastrointestinal side effects (1 of 13). CONCLUSION: This case series suggests that mTOR inhibitors can improve seizures in those with TSC and refractory epilepsy. They are also an effective treatment for reducing the volume of SEGAs in patients with TSC not amenable to surgery with an acceptable side effect profile.


Assuntos
Anticonvulsivantes/uso terapêutico , Antineoplásicos/uso terapêutico , Astrocitoma/tratamento farmacológico , Epilepsia/tratamento farmacológico , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Esclerose Tuberosa/complicações , Adolescente , Astrocitoma/etiologia , Criança , Pré-Escolar , Epilepsia/etiologia , Everolimo , Feminino , Humanos , Masculino , Estudos Prospectivos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Resultado do Tratamento
11.
Hum Mutat ; 34(1): 237-47, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23033313

RESUMO

OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X-linked condition with lethality in males. Mutations in OFD1 also cause X-linked Joubert syndrome (JBTS10) and Simpson-Golabi-Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1. Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes. Analysis of clinical findings in patients with mutations revealed that oral features are the most reliable diagnostic criteria. A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability with the complete brain phenotype consisting of complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia. Although the OFD1 gene apparently escapes X-inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity, reinforcing the hypothesis that additional factors contribute to the extensive intrafamilial variability.


Assuntos
Deleção de Genes , Mutação , Síndromes Orofaciodigitais/genética , Proteínas/genética , Adolescente , Processamento Alternativo/genética , Sequência de Bases , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Análise Mutacional de DNA , Éxons/genética , Saúde da Família , Feminino , Estudos de Associação Genética/métodos , Humanos , Lactente , Íntrons/genética , Imagem por Ressonância Magnética , Masculino , Síndromes Orofaciodigitais/patologia , Linhagem , Inativação do Cromossomo X
12.
Genome Res ; 23(1): 23-33, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23034409

RESUMO

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including lncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung-transcribed 16q24.1 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development.


Assuntos
Variações do Número de Cópias de DNA , Metilação de DNA , Síndrome da Persistência do Padrão de Circulação Fetal/genética , RNA Longo não Codificante/genética , Cromatina/metabolismo , Cromossomos Humanos Par 16/genética , Ilhas de CpG , Elementos Facilitadores Genéticos , Evolução Fatal , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Impressão Genômica , Células HEK293 , Humanos , Recém-Nascido , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas Nucleares/metabolismo , Síndrome da Persistência do Padrão de Circulação Fetal/diagnóstico , Regiões Promotoras Genéticas , RNA Longo não Codificante/metabolismo , Deleção de Sequência , Transcrição Genética , Proteína Gli2 com Dedos de Zinco
13.
Am J Med Genet A ; 155A(9): 2203-11, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21834056

RESUMO

Pierpont syndrome is a multiple congenital anomaly syndrome with learning disability first described in 1998. There are only three patients with Pierpont syndrome who have previously been published in the literature. Details of a series of patients with features of this condition were therefore obtained retrospectively to better characterize its key features. These patients were noted to have distinctive shared facial characteristics, in addition to plantar fat pads and other limb abnormalities. Further individuals with equally striking hand and foot findings were identified whose facies were less characteristic, and hence we considered them unlikely to be affected with the same condition. Despite several patients with possible Pierpont syndrome having had high-resolution array CGH or SNP array, the etiology of this phenotype remains unknown. Whilst it is as yet unclear whether it is a single entity, there appears to be a group of patients in whom Pierpont syndrome may be a recognizable condition, with typical facies, particularly when smiling, and characteristic hand and foot findings.


Assuntos
Anormalidades Múltiplas/genética , Transtornos de Aprendizagem/genética , Adulto , Criança , Pré-Escolar , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento , Face/anormalidades , Facies , Feminino , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Humanos , Cariótipo , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Síndrome
14.
Orphanet J Rare Dis ; 6: 46, 2011 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-21699693

RESUMO

BACKGROUND: The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA) (OMIM 225400) is a rare inheritable connective tissue disorder characterized by a deficiency of collagen lysyl hydroxylase 1 (LH1; EC 1.14.11.4) due to mutations in PLOD1. Biochemically this results in underhydroxylation of collagen lysyl residues and, hence, an abnormal pattern of lysyl pyridinoline (LP) and hydroxylysyl pyridinoline (HP) crosslinks excreted in the urine. Clinically the disorder is characterized by hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin hyperelasticity and fragility. Severe hypotonia usually leads to delay in gross motor development, whereas cognitive development is reported to be normal. METHODS: We describe the clinical, biochemical and molecular characterisation, as well as electron microscopy findings of skin, in 15 patients newly diagnosed with this rare type of Ehlers-Danlos syndrome. RESULTS: Age at diagnosis ranged from 5 months to 27 years, with only 1/3 of the patients been diagnosed correctly in the first year of life. A similar disease frequency was found in females and males, however a broad disease severity spectrum (intra- and interfamilial), independent of molecular background or biochemical phenotype, was observed. Kyphoscoliosis, one of the main clinical features was not present at birth in 4 patients. Importantly we also noted the occurrence of vascular rupture antenatally and postnatally, as well as developmental delay in 5 patients. CONCLUSION: In view of these findings we propose that EDS VIA is a highly variable clinical entity, presenting with a broad clinical spectrum, which may also be associated with cognitive delay and an increased risk for vascular events. Genotype/phenotype association studies and additional molecular investigations in more extended EDS VIA populations will be necessary to further elucidate the cause of the variability of the disease severity.


Assuntos
Síndrome de Ehlers-Danlos/patologia , Cifose/patologia , Escoliose/patologia , Adolescente , Adulto , Aminoácidos/urina , Biópsia , Células Cultivadas , Criança , Pré-Escolar , Análise Mutacional de DNA , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Feminino , Fibroblastos/patologia , Genótipo , Humanos , Lactente , Cifose/genética , Masculino , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Fenótipo , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/genética , Escoliose/genética , Pele/patologia
15.
J Paediatr Child Health ; 47(10): 711-6, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21449900

RESUMO

AIM: This study aims to describe the phenotypic and genotypic characteristics of 45 Australian patients with tuberous sclerosis complex (TSC), to assess risk factors for intellectual disability, to compare patients with TSC1 and TSC2 mutations and to assess adherence to surveillance recommendations. METHODS: Phenotypic features were recorded in 45 patients who fulfilled established criteria for a diagnosis of definite TSC. All patients underwent TSC1 and TSC2 sequencing and multiplex ligand probe amplification. Features were compared in patients with TSC1 mutations versus TSC2 mutations. Recent surveillance was recorded at the point of first contact. Surveillance adherence was compared in the adult and paediatric cohorts. RESULTS: This cohort consisted of 31 children and 14 adults with definite TSC. The rates of TSC manifestations and TSC1 and TSC2 mutation detection rates were consistent with previous studies. There was a trend towards greater severity for patients with TSC2 mutations compared with their TSC1 counterparts, particularly for autistic spectrum disorder, but this did not reach statistical significance. The presence of seizures was shown to be a risk factor for intellectual disability (P < 0.001). Overall, 12/45 patients (27%) were not undergoing recommended surveillance at the point of first contact. Surveillance guidelines were being followed in 3/31 (11%) children compared with 9/14 (64%) adult patients (P < 0.05). CONCLUSIONS: The genotypic and phenotypic characteristics of this TSC cohort were consistent with previous studies. Surveillance rates in adult patients were significantly lower than in paediatric patients. This highlights the need for patients with TSC to undergo a focussed transition into adult services.


Assuntos
Transtornos Cognitivos/etiologia , Vigilância da População , Guias de Prática Clínica como Assunto , Esclerose Tuberosa , Adolescente , Adulto , Austrália/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo Genético/genética , Fatores de Risco , Esclerose Tuberosa/complicações , Esclerose Tuberosa/epidemiologia , Esclerose Tuberosa/genética , Esclerose Tuberosa/fisiopatologia , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética , Adulto Jovem
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