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1.
Genet Med ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31649276

RESUMO

PURPOSE: Treacher Collins syndrome (TCS) is a rare autosomal dominant mandibulofacial dysostosis, with a prevalence of 0.2-1/10,000. Features include bilateral and symmetrical malar and mandibular hypoplasia and facial abnormalities due to abnormal neural crest cell (NCC) migration and differentiation. To date, three genes have been identified: TCOF1, POLR1C, and POLR1D. Despite a large number of patients with a molecular diagnosis, some remain without a known genetic anomaly. METHODS: We performed exome sequencing for four individuals with TCS but who were negative for pathogenic variants in the known causative genes. The effect of the pathogenic variants was investigated in zebrafish. RESULTS: We identified three novel pathogenic variants in POLR1B. Knockdown of polr1b in zebrafish induced an abnormal craniofacial phenotype mimicking TCS that was associated with altered ribosomal gene expression, massive p53-associated cellular apoptosis in the neuroepithelium, and reduced number of NCC derivatives. CONCLUSION: Pathogenic variants in the RNA polymerase I subunit POLR1B might induce massive p53-dependent apoptosis in a restricted neuroepithelium area, altering NCC migration and causing cranioskeletal malformations. We identify POLR1B as a new causative gene responsible for a novel TCS syndrome (TCS4) and establish a novel experimental model in zebrafish to study POLR1B-related TCS.

2.
Am J Hum Genet ; 104(5): 914-924, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982611

RESUMO

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506∗ and p.Glu496∗ were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.

3.
Hum Mutat ; 39(12): 1875-1884, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30157302

RESUMO

SMAD2 is a downstream effector in the TGF-ß signaling pathway, which is important for pattern formation and tissue differentiation. Pathogenic variants in SMAD2 have been reported in association with arterial aneurysms and dissections and in large cohorts of subjects with complex congenital heart disease (CHD). We used whole exome sequencing (WES) to investigate the molecular cause of CHD and other congenital anomalies in three probands and of an arterial aneurysm in an additional patient. Patients 1 and 2 presented with complex CHD, developmental delay, seizures, dysmorphic features, short stature, and poor weight gain. Patient 3 was a fetus with complex CHD and heterotaxy. The fourth patient is an adult female with aortic root aneurysm and physical features suggestive of a connective tissue disorder. WES identified pathogenic truncating variants, a splice variant, and a predicted deleterious missense variant in SMAD2. We compare the phenotypes and genotypes in our patients with previously reported cases. Our data suggest two distinct phenotypes associated with pathogenic variants in SMAD2: complex CHD with or without laterality defects and other congenital anomalies, and a late-onset vascular phenotype characterized by arterial aneurysms with connective tissue abnormalities.

4.
Am J Med Genet A ; 173(6): 1539-1545, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28332275

RESUMO

The goals of this undertaking were to assess the outcomes of thyroid screening tests and adherence to thyroid screening guidelines across five Down syndrome (DS) specialty clinics in various states. Data related to thyroid screening were collected for 663 individuals across five clinics specializing in the comprehensive care of individuals with DS for a period of 1 year. Of the 663 participants, 47.7% of participants had a TSH and free T4 ordered at their DS specialty clinic visit. Approximately 19.0% (60/316) had a new thyroid disorder diagnosis made. We conclude that a sizable proportion of the patients with DS are not up-to-date on current guidelines when they present to a DS specialty clinic, while adherence to thyroid screening guidelines helps facilitate early diagnoses. Hypothyroidism is prevalent in the population, consistent with reported literature. DS specialty clinics can help patients stay current on screening guidelines.


Assuntos
Síndrome de Down/fisiopatologia , Hipotireoidismo/fisiopatologia , Doenças da Glândula Tireoide/fisiopatologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Síndrome de Down/sangue , Síndrome de Down/complicações , Feminino , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/complicações , Lactente , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Doenças da Glândula Tireoide/sangue , Doenças da Glândula Tireoide/complicações , Testes de Função Tireóidea , Glândula Tireoide/fisiopatologia , Tireotropina/sangue , Tiroxina/sangue
5.
Genet Med ; 19(9): 1040-1048, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28252636

RESUMO

PURPOSE: Evaluation of the clinician's role in the optimal interpretation of clinical exome sequencing (ES) results. METHODS: Retrospective chart review of the first 155 patients who underwent clinical ES in our Exome Clinic and direct interaction with the ordering geneticist to evaluate the process of interpretation of results. RESULTS: The most common primary indication was neurodevelopmental problems (~66%), followed by multiple congenital anomalies (~10%). Based on sequencing data, the overall diagnostic yield was 36%. After assessment by the medical geneticist, incorporation of detailed phenotypic and molecular data, and utilization of additional diagnostic modalities, the final diagnostic yield increased to 43%. Seven patients in our cohort were included in initial case series that described novel genetic syndromes, and 23% of patients were involved in subsequent research studies directly related to their results or involved in efforts to move beyond clinical ES for diagnosis. Clinical management was directly altered due to the ES findings in 12% of definitively diagnosed cases. CONCLUSIONS: Our results emphasize the usefulness of ES, demonstrate the significant role of the medical geneticist in the diagnostic process of patients undergoing ES, and illustrate the benefits of postanalytical diagnostic work-up in solving the "diagnostic odyssey." Genet Med advance online publication 02 March 2017.


Assuntos
Exoma , Prova Pericial , Testes Genéticos , Genética Médica , Sequenciamento Completo do Exoma , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Aconselhamento Genético , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Genética Médica/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Médicos , Estudos Retrospectivos , Adulto Jovem
6.
Am J Med Genet A ; 170(12): 3098-3105, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27605215

RESUMO

The main purposes of this undertaking were to determine how often patients with Down syndrome (DS) are screened for celiac disease (CD) across five DS specialty clinics, which symptoms of CD are most often reported to DS specialty providers at these clinics, and, how many individuals were diagnosed with CD by these clinics. This was accomplished by following 663 individuals with DS for 1 year, across five clinics in different states specializing in the comprehensive care of people with DS. Of the 663 participants, 114 individuals were screened for CD at their visit to a DS specialty clinic. Protracted constipation (43.2%) and refractory behavioral problems (23.7%) were symptoms most often reported to DS specialty providers. During the 1 year study period, 13 patients screened positive for CD by serology. Of those, eight underwent duodenal biopsy, and three were diagnosed with CD. We conclude that CD is an important consideration in the comprehensive care of individuals with DS. However, while symptoms are common, diagnoses are infrequent in DS specialty clinics. © 2016 Wiley Periodicals, Inc.


Assuntos
Doença Celíaca/diagnóstico , Síndrome de Down/diagnóstico , Aconselhamento Genético , Adolescente , Adulto , Biópsia , Doença Celíaca/complicações , Doença Celíaca/fisiopatologia , Criança , Pré-Escolar , Síndrome de Down/complicações , Síndrome de Down/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Adulto Jovem
7.
Am J Hum Genet ; 99(3): 728-734, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27545675

RESUMO

Via whole-exome sequencing, we identified six females from independent families with a common neurodevelopmental phenotype including developmental delay, intellectual disability, autism, hypotonia, and seizures, all with de novo predicted deleterious variants in the nuclear localization signal of Heterogeneous Nuclear Ribonucleoprotein H2, encoded by HNRNPH2, a gene located on the X chromosome. Many of the females also have seizures, psychiatric co-morbidities, and orthopedic, gastrointestinal, and growth problems as well as common dysmorphic facial features. HNRNPs are a large group of ubiquitous proteins that associate with pre-mRNAs in eukaryotic cells to produce a multitude of alternatively spliced mRNA products during development and play an important role in controlling gene expression. The failure to identify affected males, the severity of the neurodevelopmental phenotype in females, and the essential role of this gene suggests that male conceptuses with these variants may not be viable.


Assuntos
Cromossomos Humanos X/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/genética , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Sinais de Localização Nuclear , Caracteres Sexuais , Adulto , Processamento Alternativo/genética , Sequência de Aminoácidos , Animais , Transtorno Autístico/genética , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Perda do Embrião/genética , Exoma/genética , Face/anormalidades , Feminino , Frequência do Gene , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/química , Humanos , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Hipotonia Muscular/genética , Fenótipo , Convulsões/genética
8.
Am J Med Genet A ; 167A(11): 2520-6, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26249752

RESUMO

The Down Syndrome Study Group (DSSG) was founded in 2012 as a voluntary, collaborative effort with the goal of supporting evidenced-based health care guidelines for individuals with Down syndrome (DS). Since then, 5 DS specialty clinics have collected prospective, longitudinal data on medical conditions that co-occur with DS. Data were entered by clinical staff or trained designees into the National Down Syndrome Patient Database, which we created using REDCap software. In our pilot year, we enrolled 663 participants across the U.S., ages 36 days to 70 years, from multiple racial and ethnic backgrounds. Here we report: (i) the demographic distribution of participants enrolled, (ii) a detailed account of our database infrastructure, and (iii) lessons learned during our pilot year to assist future researchers with similar goals for other patient populations.


Assuntos
Bases de Dados Factuais , Síndrome de Down/epidemiologia , Estudos Multicêntricos como Assunto , Sistema de Registros , Adolescente , Adulto , Criança , Pré-Escolar , Comportamento Cooperativo , Demografia , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Interdisciplinares , Masculino , Estados Unidos/epidemiologia , Adulto Jovem
9.
Genet Med ; 16(6): 448-59, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24232412

RESUMO

PURPOSE: "Jaffe-Campanacci syndrome" describes the complex of multiple nonossifying fibromas of the long bones, mandibular giant cell lesions, and café-au-lait macules in individuals without neurofibromas. We sought to determine whether Jaffe-Campanacci syndrome is a distinct genetic entity or a variant of neurofibromatosis type 1. METHODS: We performed germline NF1, SPRED1, and GNAS1 (exon 8) mutation testing on patients with Jaffe-Campanacci syndrome or Jaffe-Campanacci syndrome-related features. We also performed somatic NF1 mutation testing on nonossifying fibromas and giant cell lesions. RESULTS: Pathogenic germline NF1 mutations were identified in 13 of 14 patients with multiple café-au-lait macules and multiple nonossifying fibromas or giant cell lesions ("classical" Jaffe-Campanacci syndrome); all 13 also fulfilled the National Institutes of Health diagnostic criteria for neurofibromatosis type 1. Somatic NF1 mutations were detected in two giant cell lesions but not in two nonossifying fibromas. No SPRED1 or GNAS1 (exon 8) mutations were detected in the seven NF1-negative patients with Jaffe-Campanacci syndrome, nonossifying fibromas, or giant cell lesions. CONCLUSION: In this study, the majority of patients with café-au-lait macules and nonossifying fibromas or giant cell lesions harbored a pathogenic germline NF1 mutation, suggesting that many Jaffe-Campanacci syndrome cases may actually have neurofibromatosis type 1. We provide the first proof of specific somatic second-hit mutations affecting NF1 in two giant cell lesions from two unrelated patients, establishing these as neurofibromatosis type 1-associated tumors.


Assuntos
Manchas Café com Leite/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Neurofibromatose 1/genética , Neurofibromina 1/genética , Adolescente , Adulto , Neoplasias Ósseas/genética , Manchas Café com Leite/patologia , Células Cultivadas , Criança , Pré-Escolar , Cromograninas , Feminino , Fibroma/genética , Mutação em Linhagem Germinativa , Humanos , Lactente , Masculino , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/patologia , Razão de Masculinidade , Adulto Jovem
10.
Am J Med Genet A ; 161A(1): 185-91, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23239472

RESUMO

Dilation or aneurysm of the ascending aorta can progress to acute aortic dissection (Thoracic Aortic Aneurysms and Aortic Dissections, TAAD). Mutations in genes encoding TGF-ß-related proteins (TGFBR1, TGFBR2, FBN1, and SMAD3) cause syndromic and inherited TAAD. SMAD4 mutations are associated with juvenile polyposis syndrome (JPS) and a combined JPS-hereditary hemorrhagic telangiectasia (HHT) known as JPS-HHT. A family with JPS-HHT was reported to have aortic root dilation and mitral valve abnormalities. We report on two patients with JPS-HHT with SMAD4 mutations associated with thoracic aortic disease. The first patient, an 11-year-old boy without Marfan syndrome features, had JPS and an apparently de novo SMAD4 mutation (c.1340_1367dup28). Echocardiography showed mild dilation of the aortic annulus and aortic root, and mild dilation of the sinotubular junction and ascending aorta. Computed tomography confirmed aortic dilation and showed small pulmonary arteriovenous malformations (PAVM). The second patient, a 34-year-old woman with colonic polyposis, HHT, and features of Marfan syndrome, had a SMAD4 mutation (c.1245_1248delCAGA). Echocardiography showed mild aortic root dilation. She also had PAVM and hepatic focal nodular hyperplasia. Her family history was significant for polyposis, HHT, thoracic aortic aneurysm, and dissection and skeletal features of Marfan syndrome in her father. These two cases confirm the association of thoracic aortic disease with JPS-HHT resulting from SMAD4 mutations. We propose that the thoracic aorta should be screened in patients with SMAD4 mutations to prevent untimely death from dissection. This report also confirms that SMAD4 mutations predispose to TAAD.


Assuntos
Aorta/fisiopatologia , Aneurisma da Aorta Torácica/etiologia , Polipose Intestinal/genética , Proteína Smad4/genética , Telangiectasia Hemorrágica Hereditária/genética , Adulto , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/genética , Criança , Ecocardiografia , Feminino , Fibrilina-1 , Fibrilinas , Humanos , Polipose Intestinal/complicações , Polipose Intestinal/diagnóstico , Masculino , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Transdução de Sinais , Proteína Smad3/genética , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/diagnóstico , Fator de Crescimento Transformador beta/genética
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