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1.
Artigo em Inglês | MEDLINE | ID: mdl-31721432

RESUMO

CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference ≥2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (≤15% each). These results suggest that, in addition to its established link with autism and intellectual disability, CHD8 causes an overgrowth phenotype, and should be considered in the differential diagnosis of patients presenting with increased height and/or head circumference in association with intellectual disability.

2.
Genet Med ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31578471

RESUMO

PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated. RESULTS: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. CONCLUSIONS: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.

3.
J Clin Endocrinol Metab ; 104(8): 3491-3500, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30817817

RESUMO

CONTEXT: The two major forms of circulating thyroid hormones (THs) are T3 and T4. T3 is regarded as the biologically active hormone because it binds to TH receptors (TRs) with greater affinity than T4. However, it is currently unclear what structural mechanisms underlie this difference in affinity. OBJECTIVE: Prompted by the identification of a novel M256T mutation in a resistance to TH (RTH)α patient, we investigated Met256 in TRα1 and the corresponding residue (Met310) in TRß1, residues previously predicted by crystallographic studies in discrimination of T3 vs T4. METHODS: Clinical characterization of the RTHα patient and molecular studies (in silico protein modeling, radioligand binding, transactivation, and receptor-cofactor studies) were performed. RESULTS: Structural modeling of the TRα1-M256T mutant showed that distortion of the hydrophobic niche to accommodate the outer ring of ligand was more pronounced for T3 than T4, suggesting that this substitution has little impact on the affinity for T4. In agreement with the model, TRα1-M256T selectively reduced the affinity for T3. Also, unlike other naturally occurring TRα mutations, TRα1-M256T had a differential impact on T3- vs T4-dependent transcriptional activation. TRα1-M256A and TRß1-M310T mutants exhibited similar discordance for T3 vs T4. CONCLUSIONS: Met256-TRα1/Met310-TRß1 strongly potentiates the affinity of TRs for T3, thereby largely determining that T3 is the bioactive hormone rather than T4. These observations provide insight into the molecular basis for underlying the different affinity of TRs for T3 vs T4, delineating a fundamental principle of TH signaling.

4.
Neurobiol Dis ; 121: 187-204, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30296617

RESUMO

Loss-of-function mutations in the recycling endosomal (Na+,K+)/H+ exchanger gene SLC9A6/NHE6 result in overacidification and dysfunction of endosomal-lysosomal compartments, and cause a neurodevelopmental and degenerative form of X-linked intellectual disability called Christianson Syndrome (CS). However, knowledge of the disease heterogeneity of CS is limited. Here, we describe the clinical features and underlying molecular and cellular mechanisms associated with a CS patient carrying a de novo missense variant (p.Gly218Arg; G218R) of a conserved residue in its ion translocation domain that results in a potential gain-of-function. The patient manifested several core symptoms typical of CS, including pronounced cognitive impairment, mutism, epilepsy, ataxia and microcephaly; however, deterioration of motor function often observed after the first decade of life in CS children with total loss of SLC9A6/NHE6 function was not evident. In transfected non-neuronal cells, complex glycosylation and half-life of the G218R were significantly decreased compared to the wild-type transporter. This correlated with elevated ubiquitination and partial proteasomal-mediated proteolysis of G218R. However, a major fraction was delivered to the plasma membrane and endocytic pathways. Compared to wild-type, G218R-containing endosomes were atypically alkaline and showed impaired uptake of recycling endosomal cargo. Moreover, instead of accumulating in recycling endosomes, G218R was redirected to multivesicular bodies/late endosomes and ejected extracellularly in exosomes rather than progressing to lysosomes for degradation. Attenuated acidification and trafficking of G218R-containing endosomes were also observed in transfected hippocampal neurons, and correlated with diminished dendritic branching and density of mature mushroom-shaped spines and increased appearance of filopodia-like protrusions. Collectively, these findings expand our understanding of the genetic diversity of CS and further elucidate a critical role for SLC9A6/NHE6 in fine-tuning recycling endosomal pH and cargo trafficking, processes crucial for the maintenance of neuronal polarity and mature synaptic structures.


Assuntos
Ataxia/genética , Ataxia/patologia , Endossomos/metabolismo , Epilepsia/genética , Epilepsia/patologia , Mutação com Ganho de Função , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Microcefalia/genética , Microcefalia/patologia , Neurônios/patologia , Transtornos da Motilidade Ocular/genética , Transtornos da Motilidade Ocular/patologia , Trocadores de Sódio-Hidrogênio/genética , Adulto , Animais , Atrofia , Cricetulus , Dendritos/patologia , Vesículas Extracelulares/metabolismo , Células HeLa , Hipocampo/patologia , Humanos , Masculino , Mutação de Sentido Incorreto , Trocadores de Sódio-Hidrogênio/química , Adulto Jovem
6.
Front Genet ; 9: 400, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30369941

RESUMO

Mitochondrial disorders, characterized by clinical symptoms and/or OXPHOS deficiencies, are caused by pathogenic variants in mitochondrial genes. However, pathogenic variants in some of these genes can lead to clinical manifestations which overlap with other neuromuscular diseases, which can be caused by pathogenic variants in non-mitochondrial genes as well. Mitochondrial pathogenic variants can be found in the mitochondrial DNA (mtDNA) or in any of the 1,500 nuclear genes with a mitochondrial function. We have performed a two-step next-generation sequencing approach in a cohort of 117 patients, mostly children, in whom a mitochondrial disease-cause could likely or possibly explain the phenotype. A total of 86 patients had a mitochondrial disorder, according to established clinical and biochemical criteria. The other 31 patients had neuromuscular symptoms, where in a minority a mitochondrial genetic cause is present, but a non-mitochondrial genetic cause is more likely. All patients were screened for pathogenic variants in the mtDNA and, if excluded, analyzed by whole exome sequencing (WES). Variants were filtered for being pathogenic and compatible with an autosomal or X-linked recessive mode of inheritance in families with multiple affected siblings and/or consanguineous parents. Non-consanguineous families with a single patient were additionally screened for autosomal and X-linked dominant mutations in a predefined gene-set. We identified causative pathogenic variants in the mtDNA in 20% of the patient-cohort, and in nuclear genes in 49%, implying an overall yield of 68%. We identified pathogenic variants in mitochondrial and non-mitochondrial genes in both groups with, obviously, a higher number of mitochondrial genes affected in mitochondrial disease patients. Furthermore, we show that 31% of the disease-causing genes in the mitochondrial patient group were not included in the MitoCarta database, and therefore would have been missed with MitoCarta based gene-panels. We conclude that WES is preferable to panel-based approaches for both groups of patients, as the mitochondrial gene-list is not complete and mitochondrial symptoms can be secondary. Also, clinically and genetically heterogeneous disorders would require sequential use of multiple different gene panels. We conclude that WES is a comprehensive and unbiased approach to establish a genetic diagnosis in these patients, able to resolve multi-genic disease-causes.

7.
Genet Med ; 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30287924

RESUMO

PURPOSE: Several studies have reported diagnostic yields up to 57% for rapid exome or genome sequencing (rES/GS) as a single test in neonatal intensive care unit (NICU) patients, but the additional yield of rES/GS compared with other available diagnostic options still remains unquantified in this population. METHODS: We retrospectively evaluated all genetic NICU consultations in a 2-year period. RESULTS: In 132 retrospectively evaluated NICU consultations 27 of 32 diagnoses (84.4%) were made using standard genetic workup. Most diagnoses (65.6%) were made within 16 days. Diagnostic ES yield was 5/29 (17.2%). Genetic diagnoses had a direct effect on clinical management in 90.6% (29/32) of patients. CONCLUSIONS: Our study shows that exome sequencing has a place in NICU diagnostics, but given the associated costs and the high yield of alternative diagnostic strategies, we recommend to first perform clinical genetic consultation.

8.
Hum Mutat ; 39(9): 1173-1192, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29907982

RESUMO

Simultaneous analysis of multiple genes using next-generation sequencing (NGS) technology has become widely available. Copy-number variations (CNVs) in disease-associated genes have emerged as a cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis. The aim of this study was to assess the diagnostic yield and the prevalence of CNVs using our panel of Hereditary Thoracic Aortic Disease (H-TAD)-associated genes. Eight hundred ten patients suspected of H-TAD were analyzed by targeted NGS analysis of 21 H-TAD associated genes. In addition, the eXome hidden Markov model (XHMM; an algorithm to identify CNVs in targeted NGS data) was used to detect CNVs in these genes. A pathogenic or likely pathogenic variant was found in 66 of 810 patients (8.1%). Of these 66 pathogenic or likely pathogenic variants, six (9.1%) were CNVs not detectable by routine NGS analysis. These CNVs were four intragenic (multi-)exon deletions in MYLK, TGFB2, SMAD3, and PRKG1, respectively. In addition, a large duplication including NOTCH1 and a large deletion encompassing SCARF2 were detected. As confirmed by additional analyses, both CNVs indicated larger chromosomal abnormalities, which could explain the phenotype in both patients. Given the clinical relevance of the identification of a genetic cause, CNV analysis using a method such as XHMM should be incorporated into the clinical diagnostic care for H-TAD patients.

9.
Hum Mutat ; 39(5): 621-634, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29392890

RESUMO

The Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-ß (TGF-ß) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-ß signaling. More recently, TGF-ß ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-ß pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-ß signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.

10.
Int J Cardiol ; 258: 243-248, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29452988

RESUMO

BACKGROUND: Thoracic aortic aneurysm (TAA) is a potentially life-threatening disorder with a strong genetic component. The number of genes implicated in TAA has increased exponentially over the last decade. Approximately 20% of patients with TAA have a positive family history. As most TAA remain asymptomatic for a long time, screening of at risk relatives is warranted to prevent complications. Existing international guidelines lack detailed instructions regarding genetic evaluation and family screening of TAA patients. We aimed to develop a consensus document to provide medical guidance for all health care professionals involved in the recognition, diagnosis and treatment of patients with thoracic aortic disease and their relatives. METHODS: A multidisciplinary panel of experts including cardiologists, cardiothoracic surgeons, clinical geneticists and general practitioners, convened to review and discuss the current literature, guidelines and clinical practice on genetic testing and family screening in TAA. RESULTS: There is a lack of high-quality evidence in the literature. This consensus statement, based on the available literature and expert opinions, summarizes our recommendations in order to standardize and optimize the cardiogenetic care for patients and families with thoracic aortic disease. In particular, we provide criteria to identify those patients most likely to have a genetic predisposition, and discuss the preferred modality and frequency of screening in their relatives. CONCLUSIONS: Age, family history, aortic size and syndromic features determine who is advised to have genetic testing as well as screening of first-degree relatives. There is a need for more prospective multicenter studies to optimize current recommendations.


Assuntos
Aneurisma da Aorta Torácica/genética , Consenso , Prova Pericial/normas , Família , Predisposição Genética para Doença/genética , Assistência ao Paciente/normas , Aneurisma da Aorta Torácica/epidemiologia , Aneurisma da Aorta Torácica/terapia , Prova Pericial/métodos , Predisposição Genética para Doença/epidemiologia , Humanos , Países Baixos/epidemiologia , Assistência ao Paciente/métodos
11.
Am J Med Genet A ; 173(8): 2108-2125, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28548707

RESUMO

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Síndrome de Lange/genética , Proteínas/genética , Síndrome de Rett/genética , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de Lange/diagnóstico , Síndrome de Lange/fisiopatologia , Exoma/genética , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Síndrome de Rett/diagnóstico , Síndrome de Rett/fisiopatologia , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia , Adulto Jovem
12.
Clin Case Rep ; 4(4): 425-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27099744

RESUMO

Severe recessive mitochondrial myopathy caused by FBXL4 gene mutations may present prenatally with polyhydramnios and cerebellar hypoplasia. Characteristic dysmorphic features are: high and arched eyebrows, triangular face, a slight upslant of palpebral fissures, and a prominent pointed chin. Metabolic investigations invariably show increased serum lactate and pyruvate levels.

13.
Hum Mutat ; 36(12): 1145-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26247899

RESUMO

We report three families with arterial aneurysms and dissections in which variants predicted to be pathogenic were identified in SMAD2. Moreover, one variant occurred de novo in a proband with unaffected parents. SMAD2 is a strong candidate gene for arterial aneurysms and dissections given its role in the TGF-ß signaling pathway. Furthermore, although SMAD2 and SMAD3 probably have functionally distinct roles in cell signaling, they are structurally very similar. Our findings indicate that SMAD2 mutations are associated with arterial aneurysms and dissections and are in accordance with the observation that patients with pathogenic variants in genes encoding proteins involved in the TGF-ß signaling pathway exhibit arterial aneurysms and dissections as key features.


Assuntos
Aneurisma Dissecante/genética , Aneurisma/genética , Artérias/metabolismo , Artérias/patologia , Mutação , Proteína Smad2/genética , Adulto , Alelos , Aneurisma/diagnóstico , Aneurisma/metabolismo , Aneurisma Dissecante/diagnóstico , Aneurisma Dissecante/metabolismo , Biologia Computacional/métodos , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Domínios e Motivos de Interação entre Proteínas , Análise de Sequência de DNA , Proteína Smad2/química , Adulto Jovem
14.
Twin Res Hum Genet ; 18(5): 591-4, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26271273

RESUMO

BACKGROUND: Hypospadias is associated with twinning. The incidence of hypospadias in monochorionic and dichorionic male twins is, however, yet to be determined. METHODS: All medical records of monochorionic and dichorionic twins admitted to our neonatal nursery between January 2004 and August 2013 were reviewed for the presence of hypospadias. RESULTS: A total of 350 monochorionic and 303 dichorionic male twins were included in the study. The incidence of hypospadias in monochorionic and dichorionic groups was 4% (14/350) and 1% (3/303) (p = .016) respectively. In 11 of the 15 twin couples, hypospadias occurred in the twin with the lowest birth weight. The rate of hypospadias in twin infants small-for-gestational-age group was 10% (6/60) compared with 2% (11/593) in the appropriate-for-gestational-age group (p = .002). In a multivariate analysis, both monochorionicity and small-for-gestational-age were independently associated with hypospadias, odds ratio 4.1 (95% confidence interval (CI): 1.1-14.7) and 6.1 (95% CI: 2.2-17.2) respectively. CONCLUSIONS: The incidence of hypospadias is four-fold higher in monochorionic twins compared with dichorionic twins. Hypospadias is also independently associated with small-for-gestational-age.


Assuntos
Hipospadia/epidemiologia , Recém-Nascido Pequeno para a Idade Gestacional , Idade Gestacional , Humanos , Incidência , Recém-Nascido de Baixo Peso , Recém-Nascido , Modelos Logísticos , Masculino , Análise Multivariada , Estudos Retrospectivos , Gêmeos Dizigóticos , Gêmeos Monozigóticos
15.
Am J Med Genet A ; 167A(8): 1884-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25900458

RESUMO

Copy number variations (CNVs) on the short arm of chromosome 19 are relatively rare. We present a patient with a tandem de novo 3.9 Mb duplication of 19p13.12p13.2 and an adjacent 288 kb deletion of 19p13.12. The CNVs were detected by genome wide SNP-array and confirmed by fluorescence in situ hybridization. Mate-pair sequencing revealed two breakpoint junctions leading to a germline tandem inverted duplication and an adjacent deletion. The patient had a major congenital heart defect and refractory edema leading to metabolic and endocrinological disturbances. Further complications occurred due to refractory chylothorax, severe inflammatory response syndrome, and repeating sepsis. After 2 months, the child died due to intractable respiratory failure. The phenotype of this patient was compared with reported patients with overlapping deletions or duplications. We conclude that the congenital heart defect, respiratory insufficiency, and abnormal neurologic examination are most likely due the contiguous gene deletion/duplication.


Assuntos
Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 19 , Humanos , Recém-Nascido , Masculino
16.
Ned Tijdschr Geneeskd ; 157(50): A6658, 2013.
Artigo em Holandês | MEDLINE | ID: mdl-24326138

RESUMO

Marfan syndrome is a multi-system disorder of dominant inheritance in which the cardiovasculature, in particular the aorta, the eyes and the skeleton are affected. Diagnostic assessment and treatment of patients who are suspected of or have Marfan syndrome should preferably be done by multidisciplinary teams such as those found in specialised Marfan syndrome centres. The practice guideline is intended for all care givers involved with the recognition, diagnosis, consultations and the medicinal and surgical treatment of Marfan patients; it includes referral criteria and information on the referral process. A diagnosis of Marfan syndrome is based on international criteria in which aortic root dilatation and dissection, ectopia lentis, an affected first-degree family member and a pathogenic FBN1 mutation are the cardinal features. Alternative diagnoses are also included in the practice guideline. Recommendations are given for the monitoring and treatment of Marfan patients during pregnancy and delivery. Advice on lifestyle is mainly focussed on sports activities.


Assuntos
Estilo de Vida , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/terapia , Equipe de Assistência ao Paciente , Humanos , Comunicação Interdisciplinar , Síndrome de Marfan/genética , Mutação , Guias de Prática Clínica como Assunto
17.
Am J Med Genet A ; 161A(5): 973-6, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23494849

RESUMO

Chudley-McCullough syndrome (CMS) is characterized by profound sensorineural hearing loss and brain anomalies. Variants in GPSM2 have recently been reported as a cause of CMS by Doherty et al. In this study we have performed exome sequencing of three CMS patients from two unrelated families from the same Dutch village. We identified one homozygous frameshift GPSM2 variants c.1473delG in all patients. We show that this variant arises from a shared, rare haplotype. Since the c.1473delG variant was found in Mennonite settlers, it likely originated in Europe. To support DNA diagnostics, we established an LOVD database for GPSM2 containing all variants thus far described.


Assuntos
Agenesia do Corpo Caloso/genética , Cistos Aracnóideos/genética , Exoma/genética , Perda Auditiva Neurossensorial/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Adolescente , Adulto , Pré-Escolar , Europa (Continente) , Feminino , Efeito Fundador , Humanos , Lactente , Masculino , Mutação , Países Baixos , América do Norte , Linhagem , Análise de Sequência de DNA
18.
Int J Cardiol ; 167(6): 2977-82, 2013 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-23000269

RESUMO

BACKGROUND: In patients with Marfan syndrome (MFS), increased aortic wall stiffening may lead to progressive aortic dilatation. Aortic Pulse Wave Velocity (PWV), a marker of wall stiffness can be assessed regionally, using in-plane multi-directional velocity-encoded MRI. This study examined the diagnostic accuracy of regional PWV for prediction of regional aortic luminal growth during 2-year follow-up in MFS patients. METHODS: In twenty-one MFS patients (mean age 36 ± 15 years, 11 male) regional PWV and aortic luminal areas were assessed by 1.5 T MRI. At 2-year follow-up, the incidence of luminal growth, defined as mean luminal diameter increase >2mm was determined for five aortic segments (S1, ascending aorta; S2, aortic arch; S3, thoracic descending aorta, S4, supra-renal and S5, infra-renal abdominal aorta). Regional PWV at baseline was considered increased when exceeding age-related normal PWV (healthy volunteers (n=26; mean age 30 ± 10 years, 15 male)) by two standard-errors. Sensitivity and specificity of regional PWV-testing for prediction of regional luminal growth were determined. RESULTS: Regional PWV at baseline was increased in 17 out of 102 segments (17%). Significant luminal growth at follow-up was reported in 14 segments (14%). The specificity of regional PWV-testing was ≥ 78% for all aortic segments, sensitivity was ≤ 33%. CONCLUSIONS: Regional PWV was significantly increased in MFS patients as compared to healthy volunteers within similar age range, in all aortic segments except the ascending aorta. Furthermore, regional PWV-assessment has moderate to high specificity for predicting absence of regional aortic luminal growth for all aortic segments in MFS patients.


Assuntos
Aorta/patologia , Imagem por Ressonância Magnética/métodos , Síndrome de Marfan/diagnóstico , Análise de Onda de Pulso/métodos , Rigidez Vascular/fisiologia , Adulto , Aorta/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Síndrome de Marfan/fisiopatologia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Método Simples-Cego , Adulto Jovem
20.
Am J Med Genet A ; 158A(9): 2152-61, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22847950

RESUMO

We describe 19 unrelated individuals with submicroscopic deletions involving 10p15.3 characterized by chromosomal microarray (CMA). Interestingly, to our knowledge, only two individuals with isolated, submicroscopic 10p15.3 deletion have been reported to date; however, only limited clinical information is available for these probands and the deleted region has not been molecularly mapped. Comprehensive clinical history was obtained for 12 of the 19 individuals described in this study. Common features among these 12 individuals include: cognitive/behavioral/developmental differences (11/11), speech delay/language disorder (10/10), motor delay (10/10), craniofacial dysmorphism (9/12), hypotonia (7/11), brain anomalies (4/6) and seizures (3/7). Parental studies were performed for nine of the 19 individuals; the 10p15.3 deletion was de novo in seven of the probands, not maternally inherited in one proband and inherited from an apparently affected mother in one proband. Molecular mapping of the 19 individuals reported in this study has identified two genes, ZMYND11 (OMIM 608668) and DIP2C (OMIM 611380; UCSC Genome Browser), mapping within 10p15.3 which are most commonly deleted. Although no single gene has been identified which is deleted in all 19 individuals studied, the deleted region in all but one individual includes ZMYND11 and the deleted region in all but one other individual includes DIP2C. There is not a clearly identifiable phenotypic difference between these two individuals and the size of the deleted region does not generally predict clinical features. Little is currently known about these genes complicating a direct genotype/phenotype correlation at this time. These data however, suggest that ZMYND11 and/or DIP2C haploinsufficiency contributes to the clinical features associated with 10p15 deletions in probands described in this study.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 10 , Telômero , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
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