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1.
Am J Hum Genet ; 102(6): 1195-1203, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861108

RESUMO

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

2.
Am J Med Genet A ; 176(4): 925-935, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29436146

RESUMO

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.

3.
Cytogenet Genome Res ; 152(3): 117-121, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28854430

RESUMO

A 41-year-old Asian woman with bilateral renal angiomyolipomas (AML) was incidentally identified to have a balanced translocation, 46,XX,t(11;12)(p15.4;q15). She had no other features or family history to suggest a diagnosis of tuberous sclerosis. Her healthy daughter had the same translocation and no renal AML at the age of 3 years. Whole-genome sequencing was performed on genomic maternal DNA isolated from blood. A targeted de novo assembly was then conducted with ABySS for chromosomes 11 and 12. Sanger sequencing was used to validate the translocation breakpoints. As a result, genomic characterization of chromosomes 11 and 12 revealed that the 11p breakpoint disrupted the NUP98 gene in intron 1, causing a separation of the promoter and transcription start site from the rest of the gene. The translocation breakpoint on chromosome 12q was located in a gene desert. NUP98 has not yet been associated with renal AML pathogenesis, but somatic NUP98 alterations are recurrently implicated in hematological malignancies, most often following a gene fusion event. We also found evidence for complex structural events involving chromosome 12, which appear to disrupt the TDG gene. We identified a TDGP1 partially processed pseudogene at 12p12.1, which adds complexity to the de novo assembly. In conclusion, this is the first report of a germline constitutional structural chromosome rearrangement disrupting NUP98 that occurred in a generally healthy woman with bilateral renal AML.


Assuntos
Angiomiolipoma/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 12/genética , Neoplasias Renais/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Translocação Genética , Adulto , Amniocentese , Análise Citogenética/métodos , Feminino , Proteínas Ligadas por GPI/genética , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas , Pseudogenes , Sítio de Iniciação de Transcrição , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/genética
5.
Nat Genet ; 46(5): 510-515, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24705253

RESUMO

Activating mutations in genes encoding phosphatidylinositol 3-kinase (PI3K)-AKT pathway components cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH, OMIM 603387). Here we report that individuals with MPPH lacking upstream PI3K-AKT pathway mutations carry de novo mutations in CCND2 (encoding cyclin D2) that are clustered around a residue that can be phosphorylated by glycogen synthase kinase 3ß (GSK-3ß). Mutant CCND2 was resistant to proteasomal degradation in vitro compared to wild-type CCND2. The PI3K-AKT pathway modulates GSK-3ß activity, and cells from individuals with PIK3CA, PIK3R2 or AKT3 mutations showed similar CCND2 accumulation. CCND2 was expressed at higher levels in brains of mouse embryos expressing activated AKT3. In utero electroporation of mutant CCND2 into embryonic mouse brains produced more proliferating transfected progenitors and a smaller fraction of progenitors exiting the cell cycle compared to cells electroporated with wild-type CCND2. These observations suggest that cyclin D2 stabilization, caused by CCND2 mutation or PI3K-AKT activation, is a unifying mechanism in PI3K-AKT-related megalencephaly syndromes.


Assuntos
Anormalidades Múltiplas/genética , Ciclina D2/genética , Hidrocefalia/genética , Malformações do Desenvolvimento Cortical/genética , Megalencefalia/genética , Polidactilia/genética , Animais , Sequência de Bases , Western Blotting , Bromodesoxiuridina , Eletroporação , Exoma/genética , Feminino , Células HEK293 , Humanos , Imuno-Histoquímica , Camundongos , Microscopia de Fluorescência , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Análise de Sequência de DNA , Síndrome
6.
Hum Genet ; 131(1): 145-56, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21800092

RESUMO

Microdeletions of 1q43q44 result in a recognizable clinical disorder characterized by moderate to severe intellectual disability (ID) with limited or no expressive speech, characteristic facial features, hand and foot anomalies, microcephaly (MIC), abnormalities (agenesis/hypogenesis) of the corpus callosum (ACC), and seizures (SZR). Critical regions have been proposed for some of the more prominent features of this disorder such as MIC and ACC, yet conflicting data have prevented precise determination of the causative genes. In this study, the largest of pure interstitial and terminal deletions of 1q43q44 to date, we characterized 22 individuals by high-resolution oligonucleotide microarray-based comparative genomic hybridization. We propose critical regions and candidate genes for the MIC, ACC, and SZR phenotypes associated with this microdeletion syndrome. Three cases with MIC had small overlapping or intragenic deletions of AKT3, an isoform of the protein kinase B family. The deletion of only AKT3 in two cases implicates haploinsufficiency of this gene in the MIC phenotype. Likewise, based on the smallest region of overlap among the affected individuals, we suggest a critical region for ACC that contains ZNF238, a transcriptional and chromatin regulator highly expressed in the developing and adult brain. Finally, we describe a critical region for the SZR phenotype which contains three genes (FAM36A, C1ORF199, and HNRNPU). Although ~90% of cases in this study and in the literature fit these proposed models, the existence of phenotypic variability suggests other mechanisms such as variable expressivity, incomplete penetrance, position effects, or multigenic factors could account for additional complexity in some cases.


Assuntos
Agenesia do Corpo Caloso/genética , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Genes/fisiologia , Microcefalia/genética , Convulsões/genética , Anormalidades Múltiplas , Adolescente , Agenesia do Corpo Caloso/patologia , Biomarcadores/metabolismo , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Deficiência Intelectual/genética , Masculino , Microcefalia/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Convulsões/patologia , Síndrome
7.
Eur J Hum Genet ; 19(9): 959-64, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21522184

RESUMO

With the clinical implementation of genomic microarrays, the detection of cryptic unbalanced rearrangements in patients with syndromic developmental delay has improved considerably. Here we report the molecular karyotyping and phenotypic description of six new unrelated patients with partially overlapping microdeletions at 10p12.31p11.21 ranging from 1.0 to 10.6 Mb. The smallest region of overlap is 306 kb, which includes WAC gene, known to be associated with microtubule function and to have a role in cell division. Another patient has previously been described with a 10 Mb deletion, partially overlapping with our six patients. All seven patients have developmental delay and a majority of the patients have abnormal behaviour and dysmorphic features, including bulbous nasal tip, deep set eyes, synophrys/thick eyebrows and full cheeks, whereas other features varied. All patients also displayed various visual impairments and six out of seven patients had cardiac malformations. Taken together with the previously reported patient, our study suggests that the detected deletions may represent a new contiguous gene syndrome caused by dosage-sensitive genes that predispose to developmental delay.


Assuntos
Cromossomos Humanos Par 10/genética , Deficiências do Desenvolvimento/genética , Deleção de Sequência/genética , Adolescente , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Síndrome
8.
J Med Genet ; 48(4): 226-34, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21398687

RESUMO

BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder predisposing humans to cutaneous and uterine leiomyomas; in 20% of affected families, type 2 papillary renal cell cancers (PRCCII) also occur with aggressive course and poor prognosis. HLRCC results from heterozygous germline mutations in the tumour suppressor fumarate hydratase (FH) gene. METHODS: As part of the French National Cancer Institute (INCa) 'Inherited predispositions to kidney cancer' network, sequence analysis and a functional study of FH were preformed in 56 families with clinically proven or suspected HLRCC and in 23 patients with isolated PRCCII (5 familial and 18 sporadic). RESULTS: The study identified 32 different germline FH mutations (15 missense, 6 frameshifts, 4 nonsense, 1 deletion/insertion, 5 splice site, and 1 complete deletion) in 40/56 (71.4%) families with proven or suspected HLRCC and in 4/23 (17.4%) probands with PRCCII alone, including 2 sporadic cases. 21 of these were novel and all were demonstrated as deleterious by significant reduction of FH enzymatic activity. In addition, 5 asymptomatic parents in 3 families were confirmed as carrying disease-causing mutations. CONCLUSIONS: This study identified and characterised 21 novel FH mutations and demonstrated that PRCCII can be the only one manifestation of HLRCC. Due to the incomplete penetrance of HLRCC, the authors propose to extend the FH mutation analysis to every patient with PRCCII occurring before 40 years of age or when renal tumour harbours characteristic histologic features, in order to discover previously ignored HLRCC affected families.


Assuntos
Carcinoma de Células Renais/genética , Fumarato Hidratase/genética , Neoplasias Renais/genética , Mutação , Adulto , Idoso , Linhagem Celular Tumoral , Códon sem Sentido , Feminino , Mutação da Fase de Leitura , Deleção de Genes , Rearranjo Gênico , Genótipo , Mutação em Linhagem Germinativa , Humanos , Mutação INDEL , Leiomiomatose/congênito , Leiomiomatose/genética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Síndromes Neoplásicas Hereditárias , Linhagem , Neoplasias Cutâneas , Neoplasias Uterinas
9.
Pediatr Cardiol ; 31(6): 872-4, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20411253

RESUMO

Both primary pulmonary artery hypertension (PPAH) and autoimmune polyendocrine syndrome (APS) are rare disorders in children. We report a boy who was diagnosed with severe PPAH at 12 years of age. He was treated with prostacyclin for 6 years, briefly with adjunct bosentan, and eventually sildenafil was added. Six years later, after his diagnosis of PPAH, he developed APS in the form of hyperthyroidism and type 1 diabetes mellitus. No mutations were identified through genetic testing of bone morphogenetic protein receptor type II and the autoimmune-regulator gene. To our knowledge this is the first description of the combination of these two extremely rare diseases in a child.


Assuntos
Hipertensão Pulmonar/etiologia , Poliendocrinopatias Autoimunes/complicações , Diagnóstico Diferencial , Progressão da Doença , Ecocardiografia , Seguimentos , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Masculino , Poliendocrinopatias Autoimunes/diagnóstico , Pressão Propulsora Pulmonar/fisiologia , Adulto Jovem
10.
Prenat Diagn ; 29(10): 966-74, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19609942

RESUMO

OBJECTIVE: To ascertain all prenatally diagnosed cases of Steroid Sulfatase (STS) deficiency in British Columbia between August 2002 and July 2007 to determine the incidence of this condition, the clinical and laboratory findings, and the risk of a contiguous gene deletion syndrome. METHODS: We reviewed the medical records of these patients to obtain detailed information about the maternal serum screening results, family history, investigations performed, and outcome of the pregnancy. RESULTS: Thirty pregnant patients were found to have a male fetus/infant with STS deficiency, giving a minimal estimated incidence of this condition of approximately 1 in 1513 males. In twenty nine cases, this condition was isolated. One patient was found to have a contiguous gene deletion syndrome. In cases of sporadic STS deficiency diagnosed prenatally, the frequency of contiguous gene deletion syndrome in this study was 1 out of 12 (8.3%). CONCLUSION: The clinical, cytogenetic and molecular data on this series of prenatally diagnosed cases of STS deficiency indicates that this is a common condition and in cases with no family history, the risk of contiguous gene deletion syndrome is significant, and warrants additional molecular genetic investigations of the mother and/or fetus.


Assuntos
Estriol/sangue , Doenças Genéticas Inatas/epidemiologia , Ictiose Ligada ao Cromossomo X/epidemiologia , Mães , Colúmbia Britânica/epidemiologia , Análise Mutacional de DNA/métodos , Feminino , Deleção de Genes , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Humanos , Ictiose Ligada ao Cromossomo X/diagnóstico , Ictiose Ligada ao Cromossomo X/genética , Incidência , Recém-Nascido , Masculino , Gravidez , Segundo Trimestre da Gravidez/sangue , Diagnóstico Pré-Natal/métodos , Estudos Retrospectivos , Síndrome
11.
Can Fam Physician ; 54(6): 877-83, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18556497

RESUMO

OBJECTIVE: To describe the clinical presentation and delays in diagnosis of patients with cystic fibrosis (CF) with the goal of raising physicians' awareness of CF and establishing baseline data for comparison with outcomes of patients who undergo newborn screening for CF. DESIGN: Retrospective review of hospital medical records and CF clinic charts of newly diagnosed CF patients younger than 18 years who had attended the CF clinic at the BC Children's Hospital in Vancouver between January 1, 1993, and January 1, 2005. Age at diagnosis of CF was ascertained for 24 adult patients diagnosed during the same period from the CF clinic at St Paul's Hospital in Vancouver, BC. SETTING: Cystic fibrosis clinic at the BC Children's Hospital. PARTICIPANTS: All newly diagnosed CF patients from mainland BC and northern Vancouver Island (N = 122). MAIN OUTCOME MEASURES: Mean age at diagnosis; mean delay in diagnosis; weight and height or length at diagnosis; vitamin E status; mean head circumference; types of symptoms before diagnosis; Pseudomonas aeruginosa status; and number of days spent in tertiary care hospitals before diagnosis. RESULTS: Excluding the adult patients and patients with meconium ileus, mean age at diagnosis of CF was 3.6 years, and mean delay in diagnosis after first symptoms was 2.1 years. Weight at diagnosis was < or = 5th percentile in 37% of cases, and height or length was < or = 5th percentile in 26% of cases. Excluding those with meconium ileus and those taking vitamin E supplementation, 70% of the children were vitamin E deficient at diagnosis. These children had a mean head circumference substantially smaller than that of children who had adequate levels of vitamin E. About 95% of children had gastrointestinal (GI) or malnutrition symptoms before diagnosis; 15% had GI symptoms only. About 81% of patients had respiratory symptoms, but only 4% had respiratory symptoms as the only evidence of CF before diagnosis. Around 9% were colonized with P aeruginosa at diagnosis. Before being diagnosed, 79% of patients had required tertiary care hospitalization for a group total of 320 hospital days. CONCLUSION: Considerable delays in diagnosis of children with CF occur when the disease is identified solely on clinical presentation. Morbidity is often severe enough to require hospital admission before CF is diagnosed. Symptoms that occurred before diagnosis were often GI or malnutritional in nature rather than respiratory, but all such symptoms were associated with diagnostic delays.


Assuntos
Fibrose Cística/diagnóstico , Adolescente , Adulto , Colúmbia Britânica/epidemiologia , Criança , Pré-Escolar , Fibrose Cística/epidemiologia , Fibrose Cística/prevenção & controle , Diagnóstico Precoce , Política de Saúde , Humanos , Incidência , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Triagem Neonatal , Estudos Retrospectivos
12.
Am J Med Genet A ; 143A(24): 2931-6, 2007 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-17955513

RESUMO

Distal 5q-trisomy has been reported in less than 30 patients, with craniosynostosis present in five. We report two new patients with distal 5q-trisomy craniosynostosis. Patient 1 had mild Kleeblattschädel with synostosis of multiple sutures together with wide and medially deviated thumbs and halluces, indicative of Pfeiffer syndrome. Cytogenetic and CGH analyses showed a karyotype of 46,XY,der(10)t(5;10)(q33;q26.3). Patient 2 had a prominent forehead and ridging of the metopic suture. Craniosynostosis of the metopic suture was shown by CT scan. Cytogenetic and CGH analyses disclosed a karyotype of 46,XX,der(17)t(5;17)(q35.1;p13.3). Of the 22 previously reported patients, all had microcephaly and 14 had an abnormal skull shape. Our results support the previous finding that distal 5q-trisomy together with an extra copy of the MSX2 gene leads to abnormal closure of sutures and craniosynostosis.


Assuntos
Cromossomos Humanos Par 5 , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Trissomia , Bandeamento Cromossômico , Facies , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Hibridização de Ácido Nucleico
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