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1.
Prenat Diagn ; 43(3): 318-327, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36688559

RESUMO

Vascular anomalies are rare disorders that encompass a group of lesions characterized by abnormal development of the lymphovascular system. Majority of these anomalies are present at birth and could potentially be detected during the prenatal period on imaging. This allows for early intervention and prompt management to improve outcomes. However, they can be difficult to diagnose, given the rarity and overlapping findings. In this review article, we provide a comprehensive overview of congenital vascular anomalies with a liberal use of images of recent cases at our center emphasizing prenatal imaging findings and the natural history of these conditions.


Assuntos
Anormalidades Cardiovasculares , Malformações Vasculares , Recém-Nascido , Feminino , Gravidez , Humanos , Ultrassonografia Pré-Natal/métodos , Diagnóstico Pré-Natal/métodos , Malformações Vasculares/diagnóstico por imagem
2.
Am J Hum Genet ; 104(3): 530-541, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30827496

RESUMO

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Transtorno Autístico/etiologia , Deficiência Intelectual/etiologia , Mutação de Sentido Incorreto , Proteínas Nucleares/genética , Adolescente , Adulto , Sequência de Aminoácidos , Transtorno Autístico/metabolismo , Transtorno Autístico/patologia , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Lactente , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Prognóstico , Homologia de Sequência , Síndrome , Adulto Jovem
3.
Am J Hum Genet ; 102(5): 985-994, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29656860

RESUMO

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.


Assuntos
Anormalidades Múltiplas/genética , Transtorno do Espectro Autista/genética , Predisposição Genética para Doença , Variação Genética , Deficiência Intelectual/genética , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal E/genética , Adolescente , Adulto , Linhagem Celular , Criança , Éxons/genética , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Acetiltransferase N-Terminal A/metabolismo , Acetiltransferase N-Terminal E/metabolismo , Linhagem , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Saccharomyces cerevisiae/metabolismo
4.
Am J Med Genet A ; 182(4): 697-704, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31876392

RESUMO

Hearing loss (HL) is an extra-skeletal manifestation of the connective tissue disorder osteogenesis imperfecta (OI). Systematic evaluation of the prevalence and characteristics of HL in COL1A1/COL1A2-related OI will contribute to a better clinical management of individuals with OI. We collected and analyzed pure-tone audiometry data from 312 individuals with OI who were enrolled in the Linked Clinical Research Centers and the Brittle Bone Disorders Consortium. The prevalence, type, and severity of HL in COL1A1/COL1A2-related OI are reported. We show that the prevalence of HL in OI is 28% and increased with age in Type I OI but not in Types III and IV. Individuals with OI Types III and IV are at a higher risk to develop HL in the first decade of life when compared to OI Type I. We also show that the prevalence of SNHL is higher in females with OI compared to males. This study reveals new insights regarding prevalence of HL in OI including a lower general prevalence of HL in COL1A1/COL1A2-related OI than previously reported (28.3 vs. 65%) and high prevalence of SNHL in females. Our data support the need in early routine hearing evaluation in all types of OI that can be adjusted to the severity of the skeletal disease.


Assuntos
Colágeno Tipo I/genética , Perda Auditiva/epidemiologia , Mutação , Osteogênese Imperfeita/fisiopatologia , Adolescente , Adulto , Criança , Cadeia alfa 1 do Colágeno Tipo I , Feminino , Genótipo , Perda Auditiva/genética , Perda Auditiva/patologia , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte/epidemiologia , Fenótipo , Adulto Jovem
5.
Am J Med Genet A ; 179(7): 1376-1382, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31069960

RESUMO

The myelin regulatory factor gene (MYRF) encodes a transcription factor that is widely expressed. There is increasing evidence that heterozygous loss-of-function variants in MYRF can lead to abnormal development of the heart, genitourinary tract, diaphragm, and lungs. Here, we searched a clinical database containing the results of 12,000 exome sequencing studies. We identified three previously unreported males with putatively deleterious variants in MYRF: one with a point mutation predicted to affect splicing and two with frameshift variants. In all cases where parental DNA was available, these variants were found to have arisen de novo. The phenotypes identified in these subjects included a variety of congenital heart defects (CHD) (hypoplastic left heart syndrome, scimitar syndrome, septal defects, and valvular anomalies), genitourinary anomalies (ambiguous genitalia, hypospadias, and cryptorchidism), congenital diaphragmatic hernia, and pulmonary hypoplasia. The phenotypes seen in our subjects overlap those described in individuals diagnosed with PAGOD syndrome [MIM# 202660], a clinically defined syndrome characterized by pulmonary artery and lung hypoplasia, agonadism, omphalocele, and diaphragmatic defects that can also be associated with hypoplastic left heart and scimitar syndrome. These cases provide additional evidence that haploinsufficiency of MYRF causes a genetic syndrome whose cardinal features include CHD, urogenital anomalies, congenital diaphragmatic hernia, and pulmonary hypoplasia. We also conclude that consideration should be given to screening individuals with PAGOD for pathogenic variants in MYRF, and that individuals with MYRF deficiency who survive the neonatal period should be monitored closely for developmental delay and intellectual disability.


Assuntos
Haploinsuficiência , Proteínas de Membrana/genética , Fenótipo , Fatores de Transcrição/genética , Sequência de Aminoácidos , Feminino , Humanos , Recém-Nascido , Masculino , Proteínas de Membrana/química , Homologia de Sequência de Aminoácidos , Fatores de Transcrição/química
6.
Proc Natl Acad Sci U S A ; 106(35): 14820-4, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19706438

RESUMO

Mutations in the HSD17B10 gene were identified in two previously described mentally retarded males. A point mutation c.776G>C was found from a survivor (SV), whereas a potent mutation, c.419C>T, was identified in another deceased case (SF) with undetectable hydroxysteroid (17beta) dehydrogenase 10 (HSD10) activity. Protein levels of mutant HSD10(R130C) in patient SF and HSD10(E249Q) in patient SV were about half that of HSD10 in normal controls. The E249Q mutation appears to affect HSD10 subunit interactions, resulting in an allosteric regulatory enzyme. For catalyzing the oxidation of allopregnanolone by NAD+ the Hill coefficient of the mutant enzyme is approximately 1.3. HSD10(E249Q) was unable to catalyze the dehydrogenation of 2-methyl-3-hydroxybutyryl-CoA and the oxidation of allopregnanolone, a positive modulator of the gamma-aminobutyric acid type A receptor, at low substrate concentrations. Neurosteroid homeostasis is critical for normal cognitive development, and there is increasing evidence that a blockade of isoleucine catabolism alone does not commonly cause developmental disabilities. The results support the theory that an imbalance in neurosteroid metabolism could be a major cause of the neurological handicap associated with hydroxysteroid (17beta) dehydrogenase 10 deficiency.


Assuntos
3-Hidroxiacil-CoA Desidrogenases/genética , Deficiência Intelectual/enzimologia , Deficiência Intelectual/genética , Isoleucina/metabolismo , Mutação Puntual , Esteroides/metabolismo , 3-Hidroxiacil-CoA Desidrogenases/química , 3-Hidroxiacil-CoA Desidrogenases/deficiência , 3-Hidroxiacil-CoA Desidrogenases/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Biocatálise , Células Cultivadas , Fibroblastos/enzimologia , Humanos , Masculino , Modelos Moleculares , Estrutura Terciária de Proteína
7.
Pediatr Blood Cancer ; 57(2): 321-3, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21360661

RESUMO

Bannayan-Riley-Ruvacalba syndrome (BRRS) belongs to the PTEN hamartoma tumor syndromes and is characterized by a high risk of malignancy in early adulthood added to local destructive effects of hamartomas in childhood. There is no standard treatment for this condition and patients are usually offered symptomatic surgical relief. Rapamycin has been reported to be effective in the management of other conditions associated with PTEN mutation. We report here a case of BRRS in a 6-year-old male with progressive loss of function of left hand and forearm associated with pain. He was treated with oral rapamycin and regained pain-free full mobility.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Malformações Arteriovenosas/tratamento farmacológico , Síndrome do Hamartoma Múltiplo/tratamento farmacológico , Sirolimo/administração & dosagem , Extremidade Superior/irrigação sanguínea , Administração Oral , Antibióticos Antineoplásicos/efeitos adversos , Malformações Arteriovenosas/etiologia , Criança , Síndrome do Hamartoma Múltiplo/complicações , Humanos , Masculino , Sirolimo/efeitos adversos
8.
Am J Med Genet A ; 152A(9): 2335-8, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20684007

RESUMO

We report here on a 25-year follow-up of cranio-meta-diaphyseal dysplasia in a 31-year-old Caucasian male, who was reported in the literature at the age of 8 years [Langer et al. (1991); Skeletal Radiol 20:37-41]. He has hyperostotic craniofacial features with protruding lower jaw and midface hypoplasia. He has the typical radiographic features of wide long tubular bones without normal metaphyseal flaring and wide short tubular bones without normal diaphyseal constriction. We describe here his clinical and radiological findings and compare his case with those published in the literature. He is the oldest reported patient with this disorder giving some insight into the natural history of this rare skeletal dysplasia.


Assuntos
Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Síndrome de Camurati-Engelmann/diagnóstico por imagem , Adulto , Anormalidades Craniofaciais/diagnóstico por imagem , Seguimentos , Humanos , Masculino , Osteocondrodisplasias/diagnóstico por imagem , Radiografia , Doenças Raras
9.
Am J Intellect Dev Disabil ; 125(6): 475-480, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-33211814

RESUMO

Although norm-referenced scores are essential to the identification of disability, they possess several features which affect their sensitivity to change. Norm-referenced scores often decrease over time among people with neurodevelopmental disorders who exhibit slower-than-average increases in ability. Further, the reliability of norm-referenced scores is lower at the tails of the distribution, resulting in floor effects and increased measurement error for people with neurodevelopmental disorders. In contrast, the person ability scores generated during the process of constructing a standardized test with item response theory are designed to assess change. We illustrate these limitations of norm-referenced scores, and relative advantages of ability scores, using data from studies of autism spectrum disorder and creatine transporter deficiency.


Assuntos
Transtornos do Neurodesenvolvimento/diagnóstico , Testes Neuropsicológicos/normas , Avaliação de Resultados em Cuidados de Saúde/normas , Psicometria/normas , Transtorno do Espectro Autista/diagnóstico , Encefalopatias Metabólicas Congênitas/diagnóstico , Criança , Creatina/deficiência , Humanos , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência
10.
Front Genet ; 10: 611, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417602

RESUMO

The clinical utility of computational phenotyping for both genetic and rare diseases is increasingly appreciated; however, its true potential is yet to be fully realized. Alongside the growing clinical and research availability of sequencing technologies, precise deep and scalable phenotyping is required to serve unmet need in genetic and rare diseases. To improve the lives of individuals affected with rare diseases through deep phenotyping, global big data interrogation is necessary to aid our understanding of disease biology, assist diagnosis, and develop targeted treatment strategies. This includes the application of cutting-edge machine learning methods to image data. As with most digital tools employed in health care, there are ethical and data governance challenges associated with using identifiable personal image data. There are also risks with failing to deliver on the patient benefits of these new technologies, the biggest of which is posed by data siloing. The Minerva Initiative has been designed to enable the public good of deep phenotyping while mitigating these ethical risks. Its open structure, enabling collaboration and data sharing between individuals, clinicians, researchers and private enterprise, is key for delivering precision public health.

11.
Genet Med ; 10(4): 267-77, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18414210

RESUMO

PURPOSE: Genomic rearrangements of chromosome 22q11.2, including the microdeletion associated with DiGeorge/velocardiofacial syndrome, are mediated by nonallelic homologous recombination between region-specific low-copy repeats. To date, only a small number of patients with 22q11.2 microduplication have been identified. METHODS: We report the identification by array-comparative genomic hybridization of 14 individuals from eight families who harbor microduplications within the 22q11.2 region. RESULTS: We have now observed a variety of microduplications, including the typical common approximately 3-Mb microduplication, approximately 1.5-Mb nested duplication, and smaller microduplications within and distal to the DiGeorge/velocardiofacial syndrome region, consistent with nonallelic homologous recombination using distinct low-copy repeats in the 22q11.2 DiGeorge/velocardiofacial syndrome region. These microduplications likely represent the predicted reciprocal rearrangements to the microdeletions characterized in the 22q11.2 region. The phenotypes seen in these individuals are generally mild and highly variable; familial transmission is frequently observed. CONCLUSIONS: These findings highlight the unbiased ability of array-comparative genomic hybridization to identify genomic imbalances and further define the molecular etiology and clinical phenotypes seen in microduplication 22q11.2 syndrome. Our findings also further support that the 22q11.2 region is highly dynamic with frequent rearrangements using alternative low-copy repeats as recombination substrates.


Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 22/genética , Duplicação Gênica , Padrões de Herança/genética , Fenótipo , Transtornos Cromossômicos/patologia , Humanos , Hibridização in Situ Fluorescente , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos
12.
Am J Med Genet A ; 146A(11): 1395-405, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18412278

RESUMO

Trisomy 14 mosaicism is a rare cytogenetic abnormality with a defined and recognizable clinical phenotype. We present a detailed clinical history and physical findings of five patients with low-level mosaicism of trisomy 14 detected by array-based comparative genomic hybridization (array-CGH) analysis or by routine chromosome analysis. These patients exhibited growth and developmental delays with variable severity, congenital anomalies, pigmentary skin lesions, and dysmorphic features. The phenotype of our patients was compared with previously described cases. This report suggests that trisomy 14 mosaicism may be more common than has been previously appreciated and also illustrates the important application of array-CGH to detect low-level mosaic chromosome abnormalities. We predict that a wider application of the array-CGH technology will significantly increase the detection rate of low-level mosaicism and will subsequently improve our ability to provide a diagnosis for patients with dysmorphic features, congenital anomalies, and developmental delay.


Assuntos
Cromossomos Humanos Par 14 , Mosaicismo , Fenótipo , Trissomia , Criança , Pré-Escolar , Análise Citogenética , Deficiências do Desenvolvimento/etiologia , Insuficiência de Crescimento/etiologia , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Pigmentação da Pele
13.
Mol Genet Genomic Med ; 5(2): 117-121, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28361097

RESUMO

BACKGROUND: Aicardi syndrome is a severe neurodevelopmental disorder characterized by infantile spasms, typical chorioretinal lacunae, agenesis of the corpus callosum, and other neuronal migration defects. It has been reported recently that de novo variants in TEAD1 and OCEL1 each may cause Aicardi syndrome in a single individual of a small cohort of females with this clinical diagnosis. These data were interpreted to suggest that the clinical diagnosis of Aicardi syndrome may be genetically heterogeneous. METHODS: To investigate this further, we sequenced TEAD1 and OCEL1 coding regions using DNA from 38 clinically well-characterized girls with Aicardi syndrome. RESULTS: We did not detect the previously reported or any other deleterious variants in any of the analyzed samples. CONCLUSIONS: This suggests that the published variants represent either an extremely rare cause of Aicardi syndrome or an incidental finding.

14.
Int J Pediatr Endocrinol ; 2013(1): 7, 2013 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-23496938

RESUMO

OBJECTIVES: To catalogue patients with DSD and to assess the concordance of genotype and phenotype with sex assignment at birth compared to sex assignment before and following assessment by a Gender Medicine Team (GMT) at one institution, as an initial step in formulating standardized guidelines for management of these conditions. DESIGN: After obtaining IRB approval, a retrospective chart review was conducted patients seen in the Gender Medicine Clinic (GMC) between 2006-2009 at Texas Children's Hospital (TCH), Houston, Texas. McNemar's test and Kappa agreement provided associations of various factors with sex assignment at birth prior to GMT assessment and after GMT assessment. PARTICIPANTS: Forty-seven patients seen in the GMC with confirmed DSD. RESULTS: Forty-seven patients met the inclusion criteria. The mean age of the patients at the time of GMT evaluation was 9.1+/-6.1 years; 61.7% had male karyotype, and 38.3% had female karyotype; 51.1% had a male external phenotype, 42.6% had a female external phenotype, and 6.4% had phenotypic ambiguity. Sex assignment was concordant with genotype and phenotype in 63.8% and 86.4%, respectively of cases at the time of birth and in 76.6% and 97.7%, respectively, of cases after assessment by GMT. CONCLUSION: Long-term outcomes are needed to establish standardized practice guidelines for decision-making.

16.
Clin EEG Neurosci ; 43(1): 64-7, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22423553

RESUMO

Untreated maple syrup urine disease (MSUD) leads to encephalopathy in neonates and causes abnormalities on the electroencephalogram (EEG). A case is presented of MSUD with unique features consisting of a comb-like rhythm before the therapy and its disappearance with therapy is presented. This case illustrates the potential use of the EEG in the identification of this specific cause of a neonatal encephalopathy.


Assuntos
Relógios Biológicos , Encéfalo/fisiopatologia , Doença da Urina de Xarope de Bordo/diagnóstico , Doença da Urina de Xarope de Bordo/fisiopatologia , Humanos , Recém-Nascido , Masculino
17.
Eur J Hum Genet ; 20(8): 852-6, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22378287

RESUMO

Developmental delay/intellectual disabilities, speech disturbance, pre- and postnatal growth retardation, microcephaly, signs of ectodermal dysplasia, and genital malformations in males (hypospadias) represent the phenotypic core of the recent emerging 19q13.11 deletion syndrome. Using array-CGH for genome-wide screening we detected an interstitial deletion of chromosome band 19q13.11 in two patients exhibiting the recognizable pattern of malformations as described in other instances of this submicroscopic genomic imbalance. The deletion detected in our patients has been compared with previously reported cases leading to the refinement of the minimal overlapping region (MOR) for this microdeletion syndrome to 324 kb. This region encompasses five genes: four zinc finger (ZNF) genes belonging to the KRAB-ZNF subfamily (ZNF302, ZNF181, ZNF599, and ZNF30) and LOC400685. On the basis of our male patient 1 and on further six male cases of the literature, we also highlighted that larger 19q13.11 deletions including the Wilms tumor interacting protein (WTIP) gene, proximal to the MOR, results in hypospadias making this gene a possible candidate for this genital abnormality due to its well-known interaction with WT1. Although the mechanism underlying the phenotypic effects of copy number alterations involving KRAB-ZNF genes at 19q13.11 has not clearly been established, we suggest their haploinsufficiency as the most likely candidate for the phenotypic core of the 19q13.11 deletion syndrome. In addition, we hypothesized WTIP gene haploinsufficiency as responsible for hypospadias.


Assuntos
Proteínas de Transporte/genética , Deleção Cromossômica , Cromossomos Humanos Par 19 , Proteínas de Ligação a DNA/genética , Haploinsuficiência , Hipospadia/genética , ATPases Associadas a Diversas Atividades Celulares , Adolescente , Criança , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Fácies , Feminino , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/genética , Masculino
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