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1.
J Clin Invest ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31513549

RESUMO

Myocardin (MYOCD) is the founding member of a class of transcriptional co-activators that bind serum response factor to activate gene expression programs critical in smooth muscle (SM) and cardiac muscle development. Insights into the molecular functions of MYOCD have been obtained from cell culture studies and, to date, knowledge about in vivo roles of MYOCD comes exclusively from experimental animals. Here, we defined an often lethal congenital human disease associated with inheritance of pathogenic MYOCD variants. This disease manifested as a massively dilated urinary bladder, or megabladder, with disrupted SM in its wall. We provided evidence that monoallelic loss-of-function variants in MYOCD caused congenital megabladder in males only, whereas biallelic variants were associated with disease in both sexes, with a phenotype additionally involving the cardiovascular system. These results were supported by co-segregation of MYOCD variants with the phenotype in four unrelated families, by in vitro transactivation studies where pathogenic variants resulted in abrogated SM gene expression, and finding megabladder in two distinct mouse models with reduced Myocd activity. In conclusion, we have demonstrated that variants in MYOCD result in human disease, and the collective findings highlight a vital role for MYOCD in mammalian organogenesis.

2.
Genet Med ; 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31239556

RESUMO

PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

3.
Nat Commun ; 10(1): 1477, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30931947

RESUMO

Phenotypic and biochemical categorization of humans with detrimental variants can provide valuable information on gene function. We illustrate this with the identification of two different homozygous variants resulting in enzymatic loss-of-function in LDHD, encoding lactate dehydrogenase D, in two unrelated patients with elevated D-lactate urinary excretion and plasma concentrations. We establish the role of LDHD by demonstrating that LDHD loss-of-function in zebrafish results in increased concentrations of D-lactate. D-lactate levels are rescued by wildtype LDHD but not by patients' variant LDHD, confirming these variants' loss-of-function effect. This work provides the first in vivo evidence that LDHD is responsible for human D-lactate metabolism. This broadens the differential diagnosis of D-lactic acidosis, an increasingly recognized complication of short bowel syndrome with unpredictable onset and severity. With the expanding incidence of intestinal resection for disease or obesity, the elucidation of this metabolic pathway may have relevance for those patients with D-lactic acidosis.


Assuntos
Acidose Láctica/diagnóstico , Lactato Desidrogenases/genética , Ácido Láctico/metabolismo , Mutação com Perda de Função , Síndrome do Intestino Curto/metabolismo , Espasmos Infantis/diagnóstico , Acidose Láctica/genética , Adulto , Animais , Consanguinidade , Diagnóstico Diferencial , Homozigoto , Humanos , Lactente , Lactato Desidrogenases/deficiência , Masculino , Espasmos Infantis/genética , Peixe-Zebra
4.
Cell Stem Cell ; 24(2): 257-270.e8, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30595499

RESUMO

Self-renewal and differentiation of pluripotent murine embryonic stem cells (ESCs) is regulated by extrinsic signaling pathways. It is less clear whether cellular metabolism instructs developmental progression. In an unbiased genome-wide CRISPR/Cas9 screen, we identified components of a conserved amino-acid-sensing pathway as critical drivers of ESC differentiation. Functional analysis revealed that lysosome activity, the Ragulator protein complex, and the tumor-suppressor protein Folliculin enable the Rag GTPases C and D to bind and seclude the bHLH transcription factor Tfe3 in the cytoplasm. In contrast, ectopic nuclear Tfe3 represses specific developmental and metabolic transcriptional programs that are associated with peri-implantation development. We show differentiation-specific and non-canonical regulation of Rag GTPase in ESCs and, importantly, identify point mutations in a Tfe3 domain required for cytoplasmic inactivation as potentially causal for a human developmental disorder. Our work reveals an instructive and biomedically relevant role of metabolic signaling in licensing embryonic cell fate transitions.

5.
Genet Med ; 21(8): 1797-1807, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30679821

RESUMO

PURPOSE: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. METHODS: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. RESULTS: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. CONCLUSION: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.

6.
Clin Case Rep ; 6(5): 788-791, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29744057

RESUMO

One of the confounders in noninvasive prenatal testing (NIPT) is the vanishing twin phenomenon. Prolonged contribution to the maternal Cell-free DNA (cfDNA) pool by cytotrophoblasts representing a demised, aneuploid cotwin may lead to a false-positive outcome for a normal, viable twin. We show that a vanishing trisomy-14 twin contributes to cfDNA for more than 2 weeks after demise.

7.
Gastroenterology ; 155(1): 130-143.e15, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29604290

RESUMO

BACKGROUND & AIMS: Congenital diarrheal disorders are rare inherited intestinal disorders characterized by intractable, sometimes life-threatening, diarrhea and nutrient malabsorption; some have been associated with mutations in diacylglycerol-acyltransferase 1 (DGAT1), which catalyzes formation of triacylglycerol from diacylglycerol and acyl-CoA. We investigated the mechanisms by which DGAT1 deficiency contributes to intestinal failure using patient-derived organoids. METHODS: We collected blood samples from 10 patients, from 6 unrelated pedigrees, who presented with early-onset severe diarrhea and/or vomiting, hypoalbuminemia, and/or (fatal) protein-losing enteropathy with intestinal failure; we performed next-generation sequencing analysis of DNA from 8 patients. Organoids were generated from duodenal biopsies from 3 patients and 3 healthy individuals (controls). Caco-2 cells and patient-derived dermal fibroblasts were transfected or transduced with vectors that express full-length or mutant forms of DGAT1 or full-length DGAT2. We performed CRISPR/Cas9-guided disruption of DGAT1 in control intestinal organoids. Cells and organoids were analyzed by immunoblot, immunofluorescence, flow cytometry, chromatography, quantitative real-time polymerase chain reaction, and for the activity of caspases 3 and 7. RESULTS: In the 10 patients, we identified 5 bi-allelic loss-of-function mutations in DGAT1. In patient-derived fibroblasts and organoids, the mutations reduced expression of DGAT1 protein and altered triacylglycerol metabolism, resulting in decreased lipid droplet formation after oleic acid addition. Expression of full-length DGAT2 in patient-derived fibroblasts restored formation of lipid droplets. Organoids derived from patients with DGAT1 mutations were more susceptible to lipid-induced cell death than control organoids. CONCLUSIONS: We identified a large cohort of patients with congenital diarrheal disorders with mutations in DGAT1 that reduced expression of its product; dermal fibroblasts and intestinal organoids derived from these patients had altered lipid metabolism and were susceptible to lipid-induced cell death. Expression of full-length wildtype DGAT1 or DGAT2 restored normal lipid metabolism in these cells. These findings indicate the importance of DGAT1 in fat metabolism and lipotoxicity in the intestinal epithelium. A fat-free diet might serve as the first line of therapy for patients with reduced DGAT1 expression. It is important to identify genetic variants associated with congenital diarrheal disorders for proper diagnosis and selection of treatment strategies.


Assuntos
Diacilglicerol O-Aciltransferase/genética , Duodeno/metabolismo , Fibroblastos/metabolismo , Hipoalbuminemia/genética , Transtornos do Metabolismo dos Lipídeos/genética , Organoides/metabolismo , Enteropatias Perdedoras de Proteínas/genética , Células CACO-2 , Estudos de Casos e Controles , Caspase 3/metabolismo , Caspase 7/metabolismo , Criança , Pré-Escolar , Consanguinidade , Derme/citologia , Diacilglicerol O-Aciltransferase/deficiência , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Países Baixos , Forbóis , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Turquia
8.
J Matern Fetal Neonatal Med ; 31(16): 2188-2194, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28585870

RESUMO

OBJECTIVE: To evaluate the accuracy of prenatal neurosonography in diagnosing underlying causes of fetal ventriculomegaly, posterior fossa anomalies and microcephaly before 24 weeks' gestational age (GA) and to study the accuracy of prenatal counseling on postnatal prognosis. METHODS: A retrospective cohort study based on 146 cases of these fetal brain anomalies before 24 weeks' GA. Counseling on prognosis was compared with postnatal outcome. Data on genetic testing was analyzed. RESULTS: Out of 146 cases, 135 (92%) were diagnosed correctly before 24 weeks' GA. Accuracy was 98% (97/99) in cases with multiple anomalies and 81% (38/47) in cases with an isolated abnormality. Counseling on prognosis was correct in 143 out of 146 cases (98%). Prenatal genetic diagnostics detected an anomaly in 51/113 (45%) of cases. In 14/62 (23%) cases prenatal karyotyping was normal, but postnatal array-CGH detected a pathogenic anomaly. CONCLUSIONS: Despite the challenges of early gestation, accuracy in diagnosing and counseling fetal brain anomalies before 24 weeks' GA was high. Prenatal genetic testing is a valuable diagnostic tool and should be offered to all women with fetal brain anomalies. Considering the many different types of anomalies and diverse etiologies, a multidisciplinary approach is essential for counseling on postnatal outcome.


Assuntos
Aconselhamento , Malformações do Sistema Nervoso/diagnóstico , Segundo Trimestre da Gravidez , Diagnóstico Pré-Natal/métodos , Adulto , Aconselhamento/métodos , Aconselhamento/estatística & dados numéricos , Feminino , Testes Genéticos , Idade Gestacional , Humanos , Gravidez , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Ultrassonografia Pré-Natal
9.
J Genet Couns ; 26(6): 1348-1356, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28667567

RESUMO

Increasingly, high-risk pregnant women opt for non-invasive prenatal testing (NIPT) instead of invasive diagnostic testing. Since NIPT is less accurate than invasive testing, a normal NIPT result might leave women less reassured. A questionnaire study was performed among pregnant women with elevated risk for fetal aneuploidy based on first-trimester combined test (risk ≥1:200) or medical history, who were offered NIPT in the nationwide Dutch TRIDENT study. Pre- and post-test questionnaires (n = 682) included measures on: experiences with NIPT procedure, feelings of reassurance, anxiety (State-Trait Anxiety Inventory, STAI), child-related anxiety (PRAQ-R), and satisfaction. The majority (96.1%) were glad to have been offered NIPT. Most (68.5%) perceived the waiting time for NIPT results (mean: 15 days, range 5-32) as (much) too long. Most women with a normal NIPT result felt reassured (80.9%) or somewhat reassured (15.7%). Levels of anxiety and child-related anxiety were significantly lower after receiving a normal NIPT result as compared to the moment of intake (p < 0.001). Women with inadequate health literacy or a medical history (e.g. previous child with trisomy) experienced significantly higher post-test-result anxiety (Mean (M) STAI = 31.6 and 30.0, respectively) compared to those with adequate health literacy (M = 28.6) and no medical history (M = 28.6), indicating these women might benefit from extra information and/or guidance when communicating NIPT test-results. Introducing NIPT as an alternative to invasive testing, led to an offer that satisfied and largely reassured high-risk pregnant women.


Assuntos
Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Satisfação Pessoal , Diagnóstico Pré-Natal/psicologia , Adulto , Ansiedade/psicologia , Síndrome de Down/diagnóstico , Feminino , Alfabetização em Saúde , Humanos , Gravidez , Primeiro Trimestre da Gravidez/psicologia , Diagnóstico Pré-Natal/métodos , Inquéritos e Questionários
10.
Prenat Diagn ; 36(12): 1091-1098, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27739584

RESUMO

OBJECTIVE: To evaluate preferences and decision-making among high-risk pregnant women offered a choice between Non-Invasive Prenatal Testing (NIPT), invasive testing or no further testing. METHODS: Nationwide implementation study (TRIDENT) offering NIPT as contingent screening test for women at increased risk for fetal aneuploidy based on first-trimester combined testing (>1:200) or medical history. A questionnaire was completed after counseling assessing knowledge, attitudes and participation following the Multidimensional Measure of Informed Choice. RESULTS: A total of 1091/1253 (87%) women completed the questionnaire. Of these, 1053 (96.5%) underwent NIPT, 37 (3.4%) invasive testing and 1 (0.1%) declined testing. 91.7% preferred NIPT because of test safety. Overall, 77.9% made an informed choice, 89.8% had sufficient knowledge and 90.5% had positive attitudes towards NIPT. Women with intermediate (odds ratio (OR) = 3.51[1.70-7.22], p < 0.001) or high educational level (OR = 4.36[2.22-8.54], p < 0.001) and women with adequate health literacy (OR = 2.60[1.36-4.95], p = 0.004) were more likely to make an informed choice. Informed choice was associated with less decisional conflict and less anxiety (p < 0.001). Intention to terminate the pregnancy for Down syndrome was higher among women undergoing invasive testing (86.5%) compared to those undergoing NIPT (58.4%) (p < 0.001). CONCLUSIONS: The majority of women had sufficient knowledge and made an informed choice. Continuous attention for counseling is required, especially for low-educated and less health-literate women. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.


Assuntos
Ansiedade/psicologia , Atitude Frente a Saúde , Transtornos Cromossômicos/diagnóstico , Conflito (Psicologia) , DNA/sangue , Tomada de Decisões , Alfabetização em Saúde , Análise de Sequência de DNA/métodos , Adulto , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 18 , Síndrome de Down/diagnóstico , Escolaridade , Reações Falso-Positivas , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Países Baixos , Gravidez , Primeiro Trimestre da Gravidez , Inquéritos e Questionários , Fatores de Tempo , Trissomia/diagnóstico , Síndrome da Trissomia do Cromossomo 13 , Síndrome da Trissomía do Cromossomo 18 , Adulto Jovem
11.
Rheumatology (Oxford) ; 55(5): 902-10, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26867732

RESUMO

OBJECTIVE: To determine the genotype-phenotype association in patients with adenosine deaminase-2 (ADA2) deficiency due to identical homozygous R169Q mutations inCECR1 METHODS: We present a case series of nine ADA2-deficient patients with an identical homozygous R169Q mutation. Clinical and diagnostic data were collected and available MRI studies were reviewed. We performed genealogy and haplotype analyses and measured serum ADA2 activity. ADA2 activity values were correlated to clinical symptoms. RESULTS: Age of presentation differed widely between the nine presented patients (range: 0 months to 8 years). The main clinical manifestations were (hepato)splenomegaly (8/9), skin involvement (8/9) and neurological involvement (8/9, of whom 6 encountered stroke). Considerable variation was seen in type, frequency and intensity of other symptoms, which included aplastic anaemia, acute myeloid leukaemia and cutaneous ulcers. Common laboratory abnormalities included cytopenias and hypogammaglobulinaemia. ADA2 enzyme activity in patients was significantly decreased compared with healthy controls. ADA2 activity levels tended to be lower in patients with stroke compared with patients without stroke. Genealogical studies did not identify a common ancestor; however, based on allele frequency, a North-West European founder effect can be noted. Three patients underwent haematopoietic cell transplantation, after which ADA2 activity was restored and clinical symptoms resolved. CONCLUSION: This case series revealed large phenotypic variability in patients with ADA2 deficiency though they were homozygous for the same R169Q mutation inCECR1 Disease modifiers, including epigenetic and environmental factors, thus seem important in determining the phenotype. Furthermore, haematopoietic cell transplantation appears promising for those patients with a severe clinical phenotype.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/genética , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Mutação , Imunodeficiência Combinada Severa/genética , Adenosina Desaminase/sangue , Adenosina Desaminase/genética , Agamaglobulinemia/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Efeito Fundador , Haplótipos , Homozigoto , Humanos , Imunossupressores/uso terapêutico , Lactente , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Linhagem , Fenótipo , Imunodeficiência Combinada Severa/tratamento farmacológico
12.
Genet Med ; 18(9): 914-23, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26820064

RESUMO

PURPOSE: We aimed to determine the prevalence and phenotypic spectrum of NOTCH1 mutations in left-sided congenital heart disease (LS-CHD). LS-CHD includes aortic valve stenosis, a bicuspid aortic valve, coarctation of the aorta, and hypoplastic left heart syndrome. METHODS: NOTCH1 was screened for mutations in 428 nonsyndromic probands with LS-CHD, and family histories were obtained for all. When a mutation was detected, relatives were also tested. RESULTS: In 148/428 patients (35%), LS-CHD was familial. Fourteen mutations (3%; 5 RNA splicing mutations, 8 truncating mutations, 1 whole-gene deletion) were detected, 11 in familial disease (11/148 (7%)) and 3 in sporadic disease (3/280 (1%)). Forty-nine additional mutation carriers were identified among the 14 families, of whom 12 (25%) were asymptomatic. Most of these mutation carriers had LS-CHD, but 9 (18%) had right-sided congenital heart disease (RS-CHD) or conotruncal heart disease (CTD). Thoracic aortic aneurysms (TAAs) occurred in 6 mutation carriers (probands included 6/63 (10%)). CONCLUSION: Pathogenic mutations in NOTCH1 were identified in 7% of familial LS-CHD and in 1% of sporadic LS-CHD. The penetrance is high; a cardiovascular malformation was found in 75% of NOTCH1 mutation carriers. The phenotypic spectrum includes LS-CHD, RS-CHD, CTD, and TAA. Testing NOTCH1 for an early diagnosis in LS-CHD/RS-CHD/CTD/TAA is warranted.Genet Med 18 9, 914-923.


Assuntos
Cardiopatias Congênitas/genética , Insuficiência Cardíaca/genética , Síndrome do Coração Esquerdo Hipoplásico/genética , Receptor Notch1/genética , Adolescente , Adulto , Idoso , Aorta/fisiopatologia , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/fisiopatologia , Criança , Pré-Escolar , Feminino , Cardiopatias Congênitas/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Síndrome do Coração Esquerdo Hipoplásico/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem
13.
Am J Hum Genet ; 97(3): 493-500, 2015 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-26340335

RESUMO

CHAMP1 encodes a protein with a function in kinetochore-microtubule attachment and in the regulation of chromosome segregation, both of which are known to be important for neurodevelopment. By trio whole-exome sequencing, we have identified de novo deleterious mutations in CHAMP1 in five unrelated individuals affected by intellectual disability with severe speech impairment, motor developmental delay, muscular hypotonia, and similar dysmorphic features including short philtrum and a tented upper and everted lover lip. In addition to two frameshift and one nonsense mutations, we found an identical nonsense mutation, c.1192C>T (p.Arg398*), in two affected individuals. All mutations, if resulting in a stable protein, are predicted to lead to the loss of the functionally important zinc-finger domains in the C terminus of the protein, which regulate CHAMP1 localization to chromosomes and the mitotic spindle, thereby providing a mechanistic understanding for their pathogenicity. We thus establish deleterious de novo mutations in CHAMP1 as a cause of intellectual disability.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Proteínas Cromossômicas não Histona/genética , Códon sem Sentido/genética , Deficiência Intelectual/genética , Fosfoproteínas/genética , Distúrbios da Fala/genética , Sequência de Bases , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Análise de Sequência de DNA
14.
Am J Med Genet A ; 167A(9): 1983-92, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26033782

RESUMO

Robin sequence (RS) can be defined as the combination of micrognathia and upper airway obstruction/glossoptosis causing neonatal respiratory problems, with or without a cleft palate and either isolated or non-isolated. Pathogenesis varies widely. We hypothesize that optimal treatment depends on pathogenesis and therefore patients should be stratified according to diagnosis. Here, we evaluate diagnoses and (presumed) pathogeneses in an RS cohort. Medical records of all RS patients presenting between 1995-2013 in three academic hospitals were evaluated. Four clinical geneticists re-evaluated all information, including initial diagnosis. Diagnoses were either confirmed, considered uncertain, or rejected. If uncertain or rejected, patients were re-evaluated. Subsequent results were re-discussed and a final conclusion was drawn. We included 191 RS patients. After re-evaluation and changing initial diagnoses in 48 of the 191 patients (25.1%), 37.7% of the cohort had isolated RS, 8.9% a chromosome anomaly, 29.3% a Mendelian disorder, and 24.1% no detectable cause. Twenty-two different Mendelian disorders were diagnosed, of which Stickler syndrome was most frequent. Stratification of diagnoses according to (presumed) pathogenic mechanism in 73 non-isolated patients with reliable diagnoses showed 43.9% to have a connective tissue dysplasia, 5.5% a neuromuscular disorder, 47.9% a multisystem disorder, and 2.7% an unknown mechanism. We diagnosed more non-isolated RS patients compared to other studies. Re-evaluation changed initial diagnosis in a quarter of patients. We suggest standardized re-evaluation of all RS patients. Despite the relatively high diagnostic yield pathogenesis could be determined in only 59.7% (71/119), due to limited insight in pathogenesis in diagnosed entities. Further studies into pathogenesis of entities causing RS are indicated.


Assuntos
Síndrome de Pierre Robin/etiologia , Síndrome de Pierre Robin/patologia , Obstrução das Vias Respiratórias/etiologia , Obstrução das Vias Respiratórias/patologia , Artrite/etiologia , Artrite/patologia , Fissura Palatina/patologia , Doenças do Tecido Conjuntivo/etiologia , Doenças do Tecido Conjuntivo/patologia , Feminino , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Micrognatismo/etiologia , Micrognatismo/patologia , Descolamento Retiniano/etiologia , Descolamento Retiniano/patologia
16.
N Engl J Med ; 369(16): 1529-36, 2013 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-24088043

RESUMO

Plastin 3 (PLS3), a protein involved in the formation of filamentous actin (F-actin) bundles, appears to be important in human bone health, on the basis of pathogenic variants in PLS3 in five families with X-linked osteoporosis and osteoporotic fractures that we report here. The bone-regulatory properties of PLS3 were supported by in vivo analyses in zebrafish. Furthermore, in an additional five families (described in less detail) referred for diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant (rs140121121) in PLS3 was found. This variant was also associated with a risk of fracture among elderly heterozygous women that was two times as high as that among noncarriers, which indicates that genetic variation in PLS3 is a novel etiologic factor involved in common, multi-factorial osteoporosis.


Assuntos
Fraturas Ósseas/genética , Glicoproteínas de Membrana/genética , Proteínas dos Microfilamentos/genética , Osteoporose/genética , Adulto , Animais , Densidade Óssea/genética , Remodelação Óssea/genética , Criança , Pré-Escolar , Feminino , Fraturas Ósseas/etiologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Heterozigoto , Humanos , Masculino , Mutação , Osteoporose/complicações , Linhagem , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto Jovem , Peixe-Zebra
17.
Prenat Diagn ; 33(4): 328-33, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23417693

RESUMO

OBJECTIVE: This study aims to analyze differences in characteristics between women who opted for invasive testing after first-trimester combined testing and those who did not. METHOD: Follow-up was performed in 20 215 combined tests conducted between 2007 and 2011 in the central region of the Netherlands. Multivariate logistic regression analysis compared variables (Down syndrome risk estimate, maternal age, previous Down syndrome pregnancy, IVF/ICSI, parity and nuchal translucency measurement) between different groups. RESULTS: 65.4% of women with a Down syndrome risk estimate ≥1 in 200 opted for invasive 49 testing. In a multivariate model, women opting for invasive testing were significantly younger (odds ratio 0.92; 95% confidence interval 0.88-0.95) and less likely to have had IVF/ICSI (odds ratio 0.57; 95% confidence interval 0.37-0.87) than women opting out on invasive testing. In this high risk group, women <36 years opted for invasive testing more frequently, regardless of their Down syndrome risk estimate magnitude. Women ≥36 years let the magnitude of the risk estimate count significantly in their decision to opt for invasive testing. CONCLUSION: Because of the dissimilarity in the offer of prenatal screening and invasive diagnosis in the Dutch prenatal screening policy, women <36 years and women >36 years make different choices when confronted with similar Down syndrome risk estimates.


Assuntos
Síndrome de Down/diagnóstico , Aceitação pelo Paciente de Cuidados de Saúde , Diagnóstico Pré-Natal , Adolescente , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Gravidez , Primeiro Trimestre da Gravidez/psicologia , Diagnóstico Pré-Natal/psicologia , Adulto Jovem
18.
Brain ; 135(Pt 8): 2506-14, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22831780

RESUMO

Mutations in the ACTA2 gene lead to diffuse and diverse vascular diseases; the Arg179His mutation is associated with an early onset severe phenotype due to global smooth muscle dysfunction. Cerebrovascular disease associated with ACTA2 mutations has been likened to moyamoya disease, but appears to have distinctive features. This study involved the analysis of neuroimaging of 13 patients with heterozygous missense mutations in ACTA2 disrupting Arg179. All patients had persistent ductus arteriosus and congenital mydriasis, and variable presentation of pulmonary hypertension, bladder and gastrointestinal problems associated with this mutation. Distinctive cerebrovascular features were dilatation of proximal internal carotid artery, occlusive disease of terminal internal carotid artery, an abnormally straight course of intracranial arteries, and absent basal 'moyamoya' collaterals. Patterns of brain injury supported both large and small vessel disease. Key differences from moyamoya disease were more widespread arteriopathy, the combination of arterial ectasia and stenosis and, importantly, absence of the typical basal 'moyamoya' collaterals. Evaluation of previously published cases suggests some of these features are also seen in the ACTA2 mutations disrupting Arg258. The observation that transition from dilated to normal/stenotic arterial calibre coincides with where the internal carotid artery changes from an elastic to muscular artery supports the hypothesis that abnormal smooth muscle cell proliferation caused by ACTA2 mutations is modulated by arterial wall components. Patients with persistent ductus arteriosus or congenital mydriasis with a label of 'moyamoya' should be re-evaluated to ensure the distinctive neuroimaging features of an ACTA2 mutation have not been overlooked. This diagnosis has prognostic and genetic implications, and mandates surveillance of other organ systems, in particular the aorta, to prevent life-threatening aortic dissection.


Assuntos
Actinas/genética , Arginina/genética , Heterozigoto , Doença de Moyamoya/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Adolescente , Adulto , Transtornos Cerebrovasculares/diagnóstico , Transtornos Cerebrovasculares/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Doença de Moyamoya/diagnóstico
19.
Hum Mutat ; 33(8): 1175-81, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22553128

RESUMO

Pachydermoperiostosis, or primary hypertrophic osteoarthropathy (PHO), is an inherited multisystem disorder, whose features closely mimic the reactive osteoarthropathy that commonly accompanies neoplastic and inflammatory pathologies. We previously described deficiency of the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD) as a cause of this condition, implicating elevated circulating prostaglandin E(2) (PGE(2)) as causative of PHO, and perhaps also as the principal mediator of secondary HO. However, PHO is genetically heterogeneous. Here, we use whole-exome sequencing to identify recessive mutations of the prostaglandin transporter SLCO2A1, in individuals lacking HPGD mutations. We performed exome sequencing of four probands with severe PHO, followed by conventional mutation analysis of SLCO2A1 in nine others. Biallelic SLCO2A1 mutations were identified in 12 of the 13 families. Affected individuals had elevated urinary PGE(2), but unlike HPGD-deficient patients, also excreted considerable quantities of the PGE(2) metabolite, PGE-M. Clinical differences between the two groups were also identified, notably that SLCO2A1-deficient individuals have a high frequency of severe anemia due to myelofibrosis. These findings reinforce the key role of systemic or local prostaglandin excess as the stimulus to HO. They also suggest that the induction or maintenance of hematopoietic stem cells by prostaglandin may depend upon transporter activity.


Assuntos
Transportadores de Ânions Orgânicos/genética , Osteoartropatia Hipertrófica Primária/etiologia , Osteoartropatia Hipertrófica Primária/genética , Mielofibrose Primária/genética , Adolescente , Adulto , Criança , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Mutação , Osteoartropatia Hipertrófica Primária/metabolismo , Prostaglandinas/metabolismo , Adulto Jovem
20.
Am J Med Genet A ; 158A(1): 166-73, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22106008

RESUMO

Loss-of-function mutations of GLI2 are associated with features at the mild end of the holoprosencephaly spectrum, including abnormal pituitary gland formation and/or function, and craniofacial abnormalities. In addition patients may have branchial arch anomalies and polydactyly. Large, microscopically visible, interstitial deletions spanning 2q14.2 have been reported in patients with multiple congenital anomalies and intellectual disability. We report here on a patient with a mild holoprosencephaly spectrum phenotype (bilateral cleft lip and palate and abnormal pituitary gland formation with panhypopituitarism) and normal psychomotor development, who was found to carry a 1.3 Mb submicroscopic heterozygous deletion in 2q14.2, encompassing the GLI2 gene. We review the genotype and phenotype of previously published probands with GLI2 aberrations. Our findings confirm the association of haploinsufficiency of GLI2 and mild HPE spectrum features. Consistent with prior reports, we observed incomplete penetrance of the deletion in the family, illustrating the multifactorial etiology of holoprosencephaly spectrum features. In addition to the holoprosencephaly spectrum features, the proband had heterotaxy of the abdominal organs. Mutations in the known heterotaxy genes (NODAL, ZIC3 and CFC1) were excluded. The deletion contains five genes, in addition to GLI2, including the EPB4.1l5 gene. Based on findings in Epb4.1l5 mutant mice we hypothesize that Epb4.1l5 is a candidate gene for the heterotaxy observed in the proband.


Assuntos
Deleção Cromossômica , Deleção de Genes , Síndrome de Heterotaxia/genética , Holoprosencefalia/genética , Fatores de Transcrição Kruppel-Like/genética , Proteínas Nucleares/genética , Criança , Cromossomos Humanos Par 2/genética , Variações do Número de Cópias de DNA , Feminino , Triagem de Portadores Genéticos , Haploinsuficiência , Humanos , Hipopituitarismo/genética , Lactente , Imagem por Ressonância Magnética , Análise em Microsséries , Mutação , Linhagem , Fenótipo , Proteína Gli2 com Dedos de Zinco
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