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1.
Am J Hum Genet ; 108(8): 1436-1449, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216551

RESUMO

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genoma Humano , Mutação , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Masculino , Análise de Sequência de DNA
2.
Pediatrics ; 147(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33372121

RESUMO

Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) is a fatty acid oxidation disorder in which the patient is unable to break down fats to produce energy. This disorder places children at risk for metabolic decompensation during periods of stress, such as routine childhood illnesses. The intent of this clinical report is to provide pediatricians with additional information regarding the acute clinical care of patients with MCADD. Although each patient with MCADD will still be expected to have a primary metabolic physician, the involvement of the primary care provider is crucial as well. Appropriate treatment of children with MCADD can lead to avoidance of morbidity and mortality.


Assuntos
Acil-CoA Desidrogenase/deficiência , Erros Inatos do Metabolismo Lipídico/terapia , Carnitina/uso terapêutico , Criança , Emergências , Hidratação , Glucose/administração & dosagem , Humanos , Hipoglicemia/etiologia , Hipoglicemia/terapia , Complicações Intraoperatórias/prevenção & controle , Erros Inatos do Metabolismo Lipídico/complicações , Erros Inatos do Metabolismo Lipídico/diagnóstico , Complicações Pós-Operatórias/prevenção & controle , Pré-Medicação , Edulcorantes/administração & dosagem
3.
Am J Hum Genet ; 107(4): 727-742, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32891193

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.


Assuntos
Proteínas de Ligação a DNA/genética , Epigênese Genética , Fatores de Transcrição Forkhead/genética , Mutação , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Sistema Urinário/metabolismo , Anormalidades Urogenitais/genética , Proteínas de Anfíbios/antagonistas & inibidores , Proteínas de Anfíbios/genética , Proteínas de Anfíbios/metabolismo , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Proteínas de Ligação a DNA/metabolismo , Família , Feminino , Fatores de Transcrição Forkhead/metabolismo , Heterozigoto , Humanos , Lactente , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Masculino , Camundongos , Camundongos Knockout , Morfolinos/genética , Morfolinos/metabolismo , Linhagem , Ligação Proteica , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Sistema Urinário/anormalidades , Anormalidades Urogenitais/metabolismo , Anormalidades Urogenitais/patologia , Sequenciamento Completo do Exoma , Xenopus
4.
J Pediatr ; 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32553838

RESUMO

OBJECTIVES: To evaluate the clinical usefulness of rapid exome sequencing (rES) in critically ill children with likely genetic disease using a standardized process at a single institution. To provide evidence that rES with should become standard of care for this patient population. STUDY DESIGN: We implemented a process to provide clinical-grade rES to eligible children at a single institution. Eligibility included (a) recommendation of rES by a consulting geneticist, (b) monogenic disorder suspected, (c) rapid diagnosis predicted to affect inpatient management, (d) pretest counseling provided by an appropriate provider, and (e) unanimous approval by a committee of 4 geneticists. Trio exome sequencing was sent to a reference laboratory that provided verbal report within 7-10 days. Clinical outcomes related to rES were prospectively collected. Input from geneticists, genetic counselors, pathologists, neonatologists, and critical care pediatricians was collected to identify changes in management related to rES. RESULTS: There were 54 patients who were eligible for rES over a 34-month study period. Of these patients, 46 underwent rES, 24 of whom (52%) had at least 1 change in management related to rES. In 20 patients (43%), a molecular diagnosis was achieved, demonstrating that nondiagnostic exomes could change medical management in some cases. Overall, 84% of patients were under 1 month old at rES request and the mean turnaround time was 9 days. CONCLUSIONS: rES testing has a significant impact on the management of critically ill children with suspected monogenic disease and should be considered standard of care for tertiary institutions who can provide coordinated genetics expertise.

5.
Mol Genet Metab Rep ; 23: 100582, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32280589

RESUMO

We report two brothers with severe global cognitive and motor delay, cortical visual impairment and sick sinus syndrome who were born to consanguineous parents. Standard genetic evaluations did not reveal the cause of their mental retardation. As expected, chromosomal microarray (CMA) revealed extensive regions of homozygosity. Exome sequencing revealed that both affected boys were homozygous for a nonsense mutation in the G-protein ß5 (GNB5) gene (NM_016194.3:c.1032C > G; Tyr344Ter), and that the parents were carriers of this mutation. No other DNA variants that were explanatory for the sick sinus or the developmental delay/intellectual disability were identified, and no other clinical parameters are likely to have contributed to this unusual combination of phenotypes. The neurologic features of our patients are more severe than those of most of the other patients previously reported with GNB5 variants, probably because of the homozygous, complete loss-of-function (nonsense/stop-gain) nature of their variant, and their clinical course has been monitored for longer duration.

6.
Am J Med Genet A ; 179(9): 1783-1790, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31294511

RESUMO

Rare individuals with 20p11.2 proximal deletions have been previously reported, with a variable phenotype that includes heterotaxy, biliary atresia, midline brain defects associated with panhypopituitarism, intellectual disability, scoliosis, and seizures. Deletions have ranged in size from 277 kb to 11.96 Mb. We describe a newborn with a de novo 2.7 Mb deletion of 20p11.22p11.21 that partially overlaps previously reported deletions and encompasses FOXA2. Her clinical findings further expand the 20p11.2 deletion phenotype to include severe midline cranial and intracranial defects such as aqueductal stenosis with hydrocephalus, mesencephalosynapsis with diencephalic-mesencephalic junction dysplasia, and pyriform aperture stenosis. We also report one individual with a missense variant in FOXA2 who had abnormal glucose homeostasis, panhypopituitarism, and endodermal organ dysfunction. Together, these findings support the critical role of FOXA2 in panhypopituitarism and midline defects.


Assuntos
Encéfalo/anormalidades , Constrição Patológica/genética , Fator 3-beta Nuclear de Hepatócito/genética , Hipopituitarismo/genética , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Deleção Cromossômica , Cromossomos Humanos Par 20/genética , Constrição Patológica/diagnóstico por imagem , Constrição Patológica/fisiopatologia , Predisposição Genética para Doença , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/genética , Hidrocefalia/fisiopatologia , Hipopituitarismo/diagnóstico por imagem , Hipopituitarismo/fisiopatologia , Recém-Nascido , Mutação de Sentido Incorreto/genética , Fenótipo , Córtex Piriforme/diagnóstico por imagem , Córtex Piriforme/fisiopatologia
7.
Hum Mutat ; 40(7): 908-925, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30817854

RESUMO

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.


Assuntos
Defeitos Congênitos da Glicosilação/genética , Proteínas de Transporte de Monossacarídeos/genética , Proteínas de Transporte de Monossacarídeos/metabolismo , Uridina Difosfato Galactose/metabolismo , Animais , Biópsia , Células CHO , Células Cultivadas , Defeitos Congênitos da Glicosilação/metabolismo , Defeitos Congênitos da Glicosilação/patologia , Cricetulus , Feminino , Humanos , Masculino , Mutação
8.
Am J Med Genet A ; 179(5): 842-845, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30828993

RESUMO

We describe a neonate with severe respiratory failure due to acinar dysplasia found by rapid exome sequencing (rES), to have a deletion containing the TBX4 gene. rES can affect patient management in the intensive care unit and should be considered in concert with lung biopsy in neonates with undifferentiated respiratory failure.


Assuntos
Células Acinares/metabolismo , Exoma , Pneumopatias/diagnóstico , Pneumopatias/genética , Deleção de Sequência , Proteínas com Domínio T/genética , Sequenciamento Completo do Exoma , Biópsia , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Recém-Nascido , Masculino
9.
Birth Defects Res ; 111(12): 822-828, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30677250

RESUMO

BACKGROUND: The teratogenic effects of prenatal alcohol exposure (PAE) have been extensively documented over the course of 45 years of research and psychiatric problems are pervasive in this population. In adults with PAE, suicidal risk is high but less is known about the suicidal risk in adolescents with fetal alcohol spectrum disorders (FASD). This study describes the prevalence of suicidal ideation and serious suicide attempts in a sample of 54 adolescents between the ages of 13 and 18 years with FASD. METHODS: Adolescents were diagnosed with FASD using the Updated Clinical Guidelines for Diagnosing Fetal Alcohol Spectrum Disorders. The Children's Interview for Psychiatric Syndromes was used to identify those adolescents who experienced suicidal ideation and/or who had made a serious suicide attempt in the last 12 months. RESULTS: The prevalence of suicidal behaviors in this sample was high with 35.2% of teens reporting incidences of suicidal ideation and 13.0% reporting at least one serious suicide attempt in the past year. This finding is in contrast to the 17.2% and 2.4% for ideation and serious attempts, respectively, reported in the general U.S. adolescent population. Alarmingly, 29.2% of males with FASD reported a serious suicide attempt which was 19½ times higher than national norms for males. No females reported attempts. Number of home placements and the presence of a depressive disorder contributed to study outcomes. CONCLUSIONS: Findings demonstrate the significant risk for suicidality in this population, particularly adolescent males, and the need to assess and treat this life threatening behavior.


Assuntos
Comportamento do Adolescente , Transtorno Depressivo , Transtornos do Espectro Alcoólico Fetal , Efeitos Tardios da Exposição Pré-Natal , Ideação Suicida , Tentativa de Suicídio/psicologia , Adolescente , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/psicologia , Feminino , Transtornos do Espectro Alcoólico Fetal/epidemiologia , Transtornos do Espectro Alcoólico Fetal/psicologia , Humanos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Prevalência , Fatores de Risco , Fatores Sexuais
10.
Mol Genet Metab ; 124(4): 254-265, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29960856

RESUMO

Glycerol kinase (GK) is a multifunctional enzyme located at the interface of carbohydrate and fat metabolism. It contributes to both central carbon metabolism and adipogenesis; specifically, through its role as the ATP-stimulated translocation promoter (ASTP). GK overexpression leads to increased ASTP activity and increased fat storage in H4IIE cells. We performed metabolic flux analysis in human GK-overexpressing H4IIE cells and found that overexpressing cells had significantly altered fluxes through central carbon and lipid metabolism including increased flux through the pentose phosphate pathway and increased production of lipids. We also observed an equal contribution of glycerol to carbohydrate metabolism in all cell lines, suggesting that GK's alternate functions rather than its enzymatic function are important for these processes. To further elucidate the contributions of the enzymatic (phosphorylation) and alternative (ASTP) functions of GK in adipogenesis, we performed experiments on mammalian GK and E. coli GK. We determined that the ASTP function of GK (which is absent in E. coli GK) plays a greater role than the enzymatic activity in these processes. These studies further emphasize GK's diverse functionality and provides fundamental insights into the multiple protein functions of glycerol kinase.


Assuntos
Adipogenia/genética , Proteínas de Transporte/genética , Glicerol Quinase/genética , Metabolismo dos Lipídeos/genética , Animais , Metabolismo dos Carboidratos/genética , Proteínas de Transporte/química , Escherichia coli/enzimologia , Regulação Enzimológica da Expressão Gênica , Glicerol/metabolismo , Glicerol Quinase/química , Humanos , Regiões Promotoras Genéticas , Ratos
11.
J Pediatr Genet ; 5(4): 220-224, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27895974

RESUMO

Craniofacial malformations include a variety of anomalies, including cleft lip with or without cleft palate, craniosynostosis, microtia, and hemifacial microsomia. All of these anomalies can be either isolated or part of a defined genetic syndrome. A clinical geneticist or genetic counselor should be a member of the craniofacial team to help determine which patients have isolated anomalies and which are likely to have a syndrome. They would then arrange for the appropriate genetic testing to confirm the diagnosis of the specific syndrome. The identification of the specific syndrome is important for the overall care of the patient (as it identifies risk for other medical problems such as congenital heart defect) that will have to be taken into account in the care of the craniofacial malformation. In addition, knowing the specific syndrome will allow the family to understand how this happened to their child and the recurrence risk for future pregnancies. With the advent of new technologies, there are now many types of genetic testing available (including, karyotype, fluorescence in situ hybridization, chromosomal microarrays, and next generation sequencing) and the medical geneticist and genetic counselor can determine which specific testing is needed for a given patient.

12.
Mol Genet Metab ; 119(3): 288-292, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27746033

RESUMO

Mathematical modeling approaches have been commonly used in complex signaling pathway studies such as the insulin signal transduction pathway. Our expanded mathematical model of the insulin signal transduction pathway was previously shown to effectively predict glucose clearance rates using mRNA levels of key components of the pathway in a mouse model. In this study, we re-optimized and applied our expanded model to study insulin sensitivity in other species and tissues (human skeletal muscle) with altered protein activities of insulin signal transduction pathway components. The model has now been optimized to predict the effect of short term exercise on insulin sensitivity for human test subjects with obesity or type II diabetes mellitus. A comparison between our extended model and the original model showed that our model better simulates the GLUT4 translocation events of the insulin signal transduction pathway and glucose uptake as a clinically relevant model output. Results from our extended model correlate with O'Gorman's published in-vivo results. This study demonstrates the ability to adapt this model to study insulin sensitivity to many biological systems (human skeletal muscle and mouse liver) with minimal changes in the model parameters.


Assuntos
Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/genética , Modelos Teóricos , Obesidade/genética , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Humanos , Insulina/genética , Camundongos , Obesidade/complicações , Obesidade/patologia , Transdução de Sinais
13.
Hum Mol Genet ; 25(R2): R86-R93, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27346519

RESUMO

Craniofacial development is an intricate process of patterning, morphogenesis, and growth that involves many tissues within the developing embryo. Genetic misregulation of these processes leads to craniofacial malformations, which comprise over one-third of all congenital birth defects. Significant advances have been made in the clinical management of craniofacial disorders, but currently very few treatments specifically target the underlying molecular causes. Here, we review recent studies in which modeling of craniofacial disorders in primary patient cells, patient-derived induced pluripotent stem cells (iPSCs), and mice have enhanced our understanding of the etiology and pathophysiology of these disorders while also advancing therapeutic avenues for their prevention.

14.
Alcohol Clin Exp Res ; 40(8): 1744-51, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27219498

RESUMO

BACKGROUND: Project Step Up proposed to reduce alcohol consumption and alcohol-related negative outcomes in adolescents with fetal alcohol spectrum disorders (FASD). METHODS: The 54 participants (30 females, 24 males) were assigned to either Project Step Up Intervention (SUI) or Control conditions and were assessed prior to intervention, immediately following intervention, and at 3-month follow-up. Adolescents in the SUI condition participated in a 6-week, 60-minute group intervention that provided alcohol education and promoted adaptive responses to alcohol-related social pressures. Caregivers attended concurrent but separate sessions on the effects of prenatal alcohol exposure on the brain and how to handle parenting challenges associated with alcohol use in teens with FASD. RESULTS: Thirty-three percent (n = 18) of adolescents were classified as light/moderate drinkers, and 67% (n = 36) were abstinent/infrequent drinkers based on their lifetime drinking histories. Results revealed a significant decrease in self-reported alcohol risk and in alcohol-related negative behaviors (Cohen's d = 1.08 and 0.99) in light/moderate drinkers in the SUI compared to the Control group. These results were partially sustained at 3-month follow-up. Furthermore, adolescents in the abstinent/infrequent group exhibited no increase in alcohol-related outcomes suggesting that the group intervention used in this study was not iatrogenic. CONCLUSIONS: The success of this treatment development study provides preliminary support for effective treatment of adolescents with FASD to prevent or reduce alcohol use and its negative consequences in this high risk population.


Assuntos
Abstinência de Álcool , Consumo de Bebidas Alcoólicas/terapia , Intervenção Médica Precoce/métodos , Transtornos do Espectro Alcoólico Fetal/diagnóstico , Transtornos do Espectro Alcoólico Fetal/terapia , Adolescente , Abstinência de Álcool/psicologia , Abstinência de Álcool/tendências , Consumo de Bebidas Alcoólicas/psicologia , Intervenção Médica Precoce/tendências , Feminino , Transtornos do Espectro Alcoólico Fetal/psicologia , Seguimentos , Humanos , Masculino , Projetos Piloto , Gravidez , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Efeitos Tardios da Exposição Pré-Natal/psicologia , Efeitos Tardios da Exposição Pré-Natal/terapia , Autorrelato , Resultado do Tratamento
15.
Hum Mutat ; 37(2): 148-54, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26507355

RESUMO

Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).


Assuntos
Anormalidades Múltiplas/genética , Perda Auditiva/genética , Deficiência Intelectual/genética , Disostose Mandibulofacial/genética , Microcefalia/genética , Mutação , Fatores de Alongamento de Peptídeos/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Motivos de Aminoácidos , Bases de Dados Genéticas , Expressão Gênica , Haploinsuficiência , Perda Auditiva/diagnóstico , Perda Auditiva/patologia , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Disostose Mandibulofacial/diagnóstico , Disostose Mandibulofacial/patologia , Microcefalia/diagnóstico , Microcefalia/patologia , Modelos Moleculares , Dados de Sequência Molecular , Penetrância , Fenótipo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Splicing de RNA , Spliceossomos/genética
16.
Mol Genet Metab Rep ; 4: 42-45, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26309814

RESUMO

Glycerol kinase deficiency (GKD) is an X-linked inborn error of metabolism at the interface of fat and carbohydrate metabolism. We report a male patient with GKD and a novel insertion of TT in exon 5 at position 378 of the GK cDNA (378-379insTT). This resulted in a premature stop codon and 0.8% normal GK activity. The mother is a carrier for this mutation and had gestational diabetes requiring insulin during this pregnancy but not in her previous pregnancy. Given the association between GKD and type 2 diabetes mellitus, it is interesting that the mother had gestational diabetes while carrying an affected fetus. Therefore, GKD is another disease where there may be a maternal-fetal interaction based on genotype. Further investigations may help elucidate the role of GKD in the carrier mother's gestational diabetes. In addition, these studies will provide better-informed counseling to families with GKD regarding the risk to carrier females.

17.
Mol Genet Metab ; 114(1): 66-72, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25468647

RESUMO

Mathematical models of biological pathways facilitate a systems biology approach to medicine. However, these models need to be updated to reflect the latest available knowledge of the underlying pathways. We developed a mathematical model of the insulin signal transduction pathway by expanding the last major previously reported model and incorporating pathway components elucidated since the original model was reported. Furthermore, we show that inputting gene expression data of key components of the insulin signal transduction pathway leads to sensible predictions of glucose clearance rates in agreement with reported clinical measurements. In one set of simulations, our model predicted that glycerol kinase knockout mice have reduced GLUT4 translocation, and consequently, reduced glucose uptake. Additionally, a comparison of our extended model with the original model showed that the added pathway components improve simulations of glucose clearance rates. We anticipate this expanded model to be a useful tool for predicting insulin sensitivity in mammalian tissues with altered expression protein phosphorylation or mRNA levels of insulin signal transduction pathway components.


Assuntos
Glucose/metabolismo , Resistência à Insulina , Insulina/metabolismo , Modelos Biológicos , Transdução de Sinais , Animais , Perfilação da Expressão Gênica , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Glicerol Quinase/genética , Resistência à Insulina/genética , Camundongos , Camundongos Knockout , Fosforilação
18.
JAMA ; 312(18): 1880-7, 2014 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-25326637

RESUMO

IMPORTANCE: Clinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders. OBJECTIVE: To report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types. DESIGN, SETTING, AND PARTICIPANTS: Clinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available. MAIN OUTCOMES AND MEASURES: Clinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES. RESULTS: Of the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2 of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants. CONCLUSIONS AND RELEVANCE: In this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted.


Assuntos
Exoma , Doenças Genéticas Inatas/diagnóstico , Técnicas de Diagnóstico Molecular , Doenças Raras/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Doenças Raras/genética , Análise de Sequência de DNA/métodos
19.
Am J Med Genet A ; 164A(12): 3076-82, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25256560

RESUMO

Deletions of chromosome 17q12 [OMIM 614527] encompass a wide range of phenotypes, including renal cysts, diabetes mellitus, pancreatic structural abnormalities, genital tract anomalies, developmental delay, learning difficulties, and more recently, autism spectrum disorder and schizophrenia. To date, gastrointestinal malformations have not been fully characterized in this syndrome. In this case report, we describe a four-year-old girl with a 17q12 microdeletion who was born with duodenal atresia, bilateral renal cysts, left kidney dysplasia, a midline cystic structure at the conus medullaris, and dysmorphic features. Both the patient and her affected father were found to have a deletion of 17q12, which encompasses the HNF1B (hepatocyte nuclear factor beta). It is hypothesized that HNF1B may play a role in intestinal differentiation and development. Our clinical report further expands the pre-and post-natal presentation of this rare microdeletion syndrome.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Aberrações Cromossômicas , Cromossomos Humanos Par 17/genética , Obstrução Duodenal/genética , Fator 1-beta Nuclear de Hepatócito/deficiência , Fenótipo , Feminino , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Atresia Intestinal , Análise em Microsséries , Síndrome
20.
Mol Genet Metab Rep ; 1: 373-377, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-27896111

RESUMO

Both adrenal catecholamines and steroids are known to be involved in the stress response, immune function, blood pressure and energy homeostasis. The response to stress is characterized by the activation of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic-adrenomedullary system, though the correlation with activation and development is not well understood. We evaluated the stress response of both cortisol and catecholamines during development in zebrafish. Zebrafish at two different stages of development were stressed in one of two different ways and cortisol and catecholamine were measured. Cortisol was measured by enzyme immune assay and catecholamine was measured by ELISA. Our results show that stress responses are delayed until after the synthesis of both cortisol and catecholamines. These observations suggest that the development of HPA axis may be required for the acquisition of the stress response for cortisol and catecholamines.

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