RESUMEN
Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.
Asunto(s)
ARN Helicasas DEAD-box/genética , Mutación Missense , Proteínas de Neoplasias/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , ARN Helicasas/genética , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Recién Nacido , Masculino , Linaje , Secuenciación del ExomaRESUMEN
PURPOSE: Reports have questioned the dogma of exclusive maternal transmission of human mitochondrial DNA (mtDNA), including the recent report of an admixture of two mtDNA haplogroups in individuals from three multigeneration families. This was interpreted as being consistent with biparental transmission of mtDNA in an autosomal dominant-like mode. The authenticity and frequency of these findings are debated. METHODS: We retrospectively analyzed individuals with two mtDNA haplogroups from 2017 to 2019 and selected four families for further study. RESULTS: We identified this phenomenon in 104/27,388 (approximately 1/263) unrelated individuals. Further study revealed (1) a male with two mitochondrial haplogroups transmits only one haplogroup to some of his offspring, consistent with nuclear transmission; (2) the heteroplasmy level of paternally transmitted variants is highest in blood, lower in buccal, and absent in muscle or urine of the same individual, indicating it is inversely correlated with mtDNA content; and (3) paternally transmitted apparent large-scale mtDNA deletions/duplications are not associated with a disease phenotype. CONCLUSION: These findings strongly suggest that the observed mitochondrial haplogroup of paternal origin resulted from coamplification of rare, concatenated nuclear mtDNA segments with genuine mtDNA during testing. Evaluation of additional specimen types can help clarify the clinical significance of the observed results.
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ADN Mitocondrial , Mitocondrias , ADN Mitocondrial/genética , Haplotipos , Humanos , Masculino , Mitocondrias/genética , Fenotipo , Estudios RetrospectivosRESUMEN
Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage-sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi-faceted complications due to haploinsufficiency of BPTF.
Asunto(s)
Ensamble y Desensamble de Cromatina/genética , Epilepsia/genética , Microcefalia/genética , Trastornos del Neurodesarrollo/genética , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Adolescente , Adulto , Niño , Preescolar , Deleción Cromosómica , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Epilepsia/fisiopatología , Facies , Femenino , Haploinsuficiencia/genética , Humanos , Lactante , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Trastornos del Desarrollo del Lenguaje/genética , Trastornos del Desarrollo del Lenguaje/fisiopatología , Masculino , Microcefalia/fisiopatología , Persona de Mediana Edad , Trastornos del Neurodesarrollo/fisiopatología , Fenotipo , Factores de Transcripción/genética , Adulto JovenRESUMEN
SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.
Asunto(s)
Proteínas de Unión a la Región de Fijación a la Matriz/genética , Mutación , Trastornos del Neurodesarrollo/genética , Factores de Transcripción/genética , Adolescente , Animales , Niño , Preescolar , Codón de Terminación , Modelos Animales de Enfermedad , Femenino , Reordenamiento Génico , Estudios de Asociación Genética , Humanos , Masculino , Mutación Missense , Polimorfismo de Nucleótido SimpleRESUMEN
Overweight/obese individuals with Type 2 diabetes have low adiponectin levels, which may improve with lifestyle changes. We investigated whether genetic variants associated with adiponectin levels in genome-wide association studies (GWAS) would also be related with adiponectin changes in response to an intensive lifestyle intervention (ILI), potentially through mechanisms altering the adipose microenvironment via weight loss and/or improved cardiorespiratory fitness. Look AHEAD was a randomized trial comparing the cardiovascular benefits of ILI-induced weight loss and physical activity compared with diabetes support and education among overweight/obese individuals with Type 2 diabetes. In a subsample of Look AHEAD with adiponectin data and genetic consent (n=1,351), we evaluated the effects of 24 genetic variants, demonstrated by GWAS to be cross-sectionally associated with adiponectin, on adiponectin change 1-yr postintervention. We explored via mediational analyses whether any differential effects by treatment arm were occurring through weight loss and/or improved fitness. A variant, rs222857, in the CLDN7 locus, potentially associated with epithelial barrier integrity and tight junction physiology, and a putative cis expression quantitative trail locus for elongator acetyltransferase complex subunit 5 (ELP5), predicted adiponectin increases within ILI (log-adiponectin in overall sample per copy: ß±SE=0.05±0.02, P=0.008; in non-Hispanic whites: 0.06±0.02, P=0.009). The favorable effects of rs222857 (minor allele frequency 45.5%) appeared to be mediated by mechanisms associated with improved fitness, and not weight loss. This is the first study to identify a genetic variant that modifies adiponectin response to lifestyle intervention in overweight/obese diabetic individuals.
Asunto(s)
Adiponectina/genética , Claudinas/genética , Diabetes Mellitus Tipo 2/genética , Estilo de Vida , Obesidad/genética , Aptitud Física , Polimorfismo de Nucleótido Simple/genética , Adiposidad/genética , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Obesidad/complicacionesRESUMEN
Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol and premature cardiovascular disease, with a prevalence of approximately 1 in 200-500 for heterozygotes in North America and Europe. Monogenic FH is largely attributed to mutations in the LDLR, APOB, and PCSK9 genes. Differential diagnosis is critical to distinguish FH from conditions with phenotypically similar presentations to ensure appropriate therapeutic management and genetic counseling. Accurate diagnosis requires careful phenotyping based on clinical and biochemical presentation, validated by genetic testing. Recent investigations to discover additional genetic loci associated with extreme hypercholesterolemia using known FH families and population studies have met with limited success. Here, we provide a brief overview of the genetic determinants, differential diagnosis, genetic testing, and counseling of FH genetics.
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Hiperlipoproteinemia Tipo II/genética , Apolipoproteína B-100/genética , Enfermedad de Acumulación de Colesterol Éster/diagnóstico , Diagnóstico Diferencial , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Hipercolesterolemia/diagnóstico , Hiperlipoproteinemia Tipo II/diagnóstico , Enfermedades Intestinales/diagnóstico , Errores Innatos del Metabolismo Lipídico/diagnóstico , Fitosteroles/efectos adversos , Proproteína Convertasa 9 , Proproteína Convertasas/genética , Receptores de LDL/genética , Serina Endopeptidasas/genética , Xantomatosis Cerebrotendinosa/diagnósticoRESUMEN
Genetic variants within the BUD13-APOA5 gene region are known to be associated with high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels. Recent studies suggest that single nucleotide polymorphisms (SNPs) within this region affect HDL-C response to statin-fibrate combination therapy and low-density lipoprotein cholesterol (LDL-C) response to statin therapy. We hypothesized that SNPs within the BUD13-APOA5 region are associated with TG, HDL-C, and LDL-C response to statin therapy. We examined 1520 observations for 1086 patients from the Personalized Medicine Research Project, a large biorepository at the Marshfield Clinic Research Foundation, who had received statin therapy and been previously genotyped for polymorphisms in the 11q23 chromosomal region. A significant differential response to statin therapy was observed for 3 SNPs. The minor allele at rs11605293 significantly attenuated TG-lowering response to pravastatin (P = 0.000159), whereas the minor allele at rs12806755 was associated with a similar response to lovastatin (P = 0.000192). Genotypes at rs947990 significantly attenuated LDL-C reduction to atorvastatin therapy (P = 0.000668) with some patients with the minor allele having LDL-C increase after therapy. No SNPs within the BUD13-APOA5 region were associated with a significant effect on HDL-C reduction in response to statin therapy. In conclusion, this study suggests that common SNPs within the BUD13-APOA5 can affect TG and LDL-C response to statin therapy in a North American population.
Asunto(s)
Apolipoproteínas A/genética , LDL-Colesterol/sangre , Variación Genética/genética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Proteínas de Unión al ARN/genética , Triglicéridos/sangre , Anciano , Anciano de 80 o más Años , Apolipoproteína A-V , HDL-Colesterol/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Resultado del TratamientoRESUMEN
Total cholesterol, low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C) levels are among the most important risk factors for coronary artery disease. We tested for gene-gene interactions affecting the level of these four lipids based on prior knowledge of established genome-wide association study (GWAS) hits, protein-protein interactions, and pathway information. Using genotype data from 9,713 European Americans from the Atherosclerosis Risk in Communities (ARIC) study, we identified an interaction between HMGCR and a locus near LIPC in their effect on HDL-C levels (Bonferroni corrected P(c)â=â0.002). Using an adaptive locus-based validation procedure, we successfully validated this gene-gene interaction in the European American cohorts from the Framingham Heart Study (P(c)â=â0.002) and the Multi-Ethnic Study of Atherosclerosis (MESA; P(c)â=â0.006). The interaction between these two loci is also significant in the African American sample from ARIC (P(c)â=â0.004) and in the Hispanic American sample from MESA (P(c)â=â0.04). Both HMGCR and LIPC are involved in the metabolism of lipids, and genome-wide association studies have previously identified LIPC as associated with levels of HDL-C. However, the effect on HDL-C of the novel gene-gene interaction reported here is twice as pronounced as that predicted by the sum of the marginal effects of the two loci. In conclusion, based on a knowledge-driven analysis of epistasis, together with a new locus-based validation method, we successfully identified and validated an interaction affecting a complex trait in multi-ethnic populations.
Asunto(s)
HDL-Colesterol/genética , Epistasis Genética , Estudio de Asociación del Genoma Completo , Hidroximetilglutaril-CoA Reductasas , Lipasa , Negro o Afroamericano , LDL-Colesterol/genética , Hispánicos o Latinos , Humanos , Hidroximetilglutaril-CoA Reductasas/genética , Lipasa/genética , Triglicéridos/genética , Población BlancaRESUMEN
Individuals with mixed dyslipidemia, including high triglycerides (TGs) and low high density lipoprotein cholesterol (HDL-C), have increased risk for coronary events. We examined the effect of rare genetic variants in the APOA5 gene region on plasma HDL-C, apolipoprotein A-I (apoA-I), and TG response to fenofibric acid monotherapy and in combination with statins. The APOA5 gene region was sequenced in 1,612 individuals with mixed dyslipidemia in a randomized trial of fenofibric acid alone and in combination with statins. Student's t-test and rare variant burden tests were used to examine plasma HDL-C, apoA-I, and TG response. Rare APOA5 promoter region variants were associated with decreased HDL-C and apoA-I levels in response to fenofibric acid therapy; rare missense variants were associated with increased TG response to combination therapy. Further study is needed to examine the effect of these rare variants on coronary outcomes in this population in response to fenofibric acid monotherapy or combined with statins.
Asunto(s)
Apolipoproteínas A/genética , HDL-Colesterol/sangre , Dislipidemias/tratamiento farmacológico , Fenofibrato/análogos & derivados , Variación Genética/genética , Regiones Promotoras Genéticas/genética , Aminoácidos/farmacología , Apolipoproteína A-I/sangre , Apolipoproteína A-V , Dislipidemias/sangre , Dislipidemias/genética , Femenino , Fenofibrato/uso terapéutico , Humanos , Masculino , Triglicéridos/sangreRESUMEN
BACKGROUND: On the basis of studies with limited statistical power, lipoprotein(a) [Lp(a)] is not considered a risk factor for cardiovascular disease (CVD) in blacks. We evaluated associations between Lp(a) and incident CVD events in blacks and whites in the Atherosclerosis Risk in Communities (ARIC) study. METHODS AND RESULTS: Plasma Lp(a) was measured in blacks (n=3467) and whites (n=9851). Hazards ratios (HRs) for incident CVD events (coronary heart disease and ischemic strokes) were calculated. Lp(a) levels were higher with wider interindividual variation in blacks (median [interquartile range], 12.8 [7.1-21.7] mg/dL) than whites (4.3 [1.7-9.5] mg/dL; P<0.0001). At 20 years of follow-up, 676 CVD events occurred in blacks, and 1821 events occurred in whites. Adjusted HRs (95% confidence interval) per race-specific 1-SD-greater log-transformed Lp(a) were 1.13 (1.04-1.23) for incident CVD, 1.11 (1.00-1.22) for incident coronary heart disease, and 1.21 (1.06-1.39) for ischemic strokes in blacks. For whites, the respective HRs (95% confidence intervals) were 1.09 (1.04-1.15), 1.10 (1.05-1.16), and 1.07 (0.97-1.19). Quintile analyses showed that risk for incident CVD was graded but statistically significant only for the highest compared with the lowest quintile (HR [95% confidence interval], 1.35 [1.06-1.74] for blacks and 1.27 [1.10-1.47] for whites). Similar results were obtained with the use of Lp(a) cutoffs of ≤10 mg/dL, >10 to ≤20 mg/dL, >20 to ≤30 mg/dL, and >30 mg/dL. CONCLUSIONS: Lp(a) levels were positively associated with CVD events. Associations were at least as strong, with a larger range of Lp(a) concentrations, in blacks compared with whites.
Asunto(s)
Enfermedades Cardiovasculares/etnología , Lipoproteína(a)/sangre , Adulto , Anciano , Aterosclerosis/diagnóstico , Aterosclerosis/etnología , Población Negra , Enfermedades Cardiovasculares/diagnóstico , Enfermedad Coronaria , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Pronóstico , Riesgo , Accidente Cerebrovascular , Población BlancaRESUMEN
The mixed dyslipidemia phenotype is characterized by elevated triglycerides (TG), low HDL cholesterol (HDL-C), increased ApoB levels, and premature coronary atherosclerosis. Fibrate-statin combination therapy reduces ApoB levels and coronary events in the mixed dyslipidemia population. We sought to identify gene-gene interactions that affect ApoB response to statin-fenofibric acid therapy in the mixed dyslipidemia population. Using a predefined subset of single-nucleotide polymorphisms (SNPs) that were previously associated with TG, VLDL, or HDL-C, we applied gene-gene interaction testing in a randomized, double-blind, clinical trial examining the response to fenofibric acid (FNA) and its combination with statin in 1,865 individuals with mixed dyslipidemia. Of 11,783 possible SNP pairs examined, we detected a single significant interaction between rs12130333, located within the ANGPTL3 gene region, and rs4240705, within the RXRA gene, on ApoB reduction after statin-FNA therapy (P = 4.0 × 10(-6)). ApoB response to therapy gradually reduced with the increasing number of T alleles in the rs12130333 but only in the presence of the GG genotype of rs4240705. Individuals doubly homozygous for the minor alleles at rs12130333 and rs4240705 showed a paradoxical increase of 1.8% in ApoB levels after FNA-statin combination therapy. No gene-gene interaction was identified other than an interaction between SNPs in the ANGPTL3 and RXRA regions, which results in the inhibition of ApoB reduction in response to statin-FNA therapy. Further study is required to examine the clinical applicability of this genetic interaction and its effect on coronary events.
Asunto(s)
Angiopoyetinas/genética , Apolipoproteínas B/metabolismo , Apolipoproteínas/metabolismo , Dislipidemias/tratamiento farmacológico , Dislipidemias/genética , Fenofibrato/análogos & derivados , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Polimorfismo de Nucleótido Simple/genética , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina , Atorvastatina , Femenino , Fenofibrato/administración & dosificación , Fenofibrato/uso terapéutico , Fluorobencenos/uso terapéutico , Ácidos Heptanoicos/uso terapéutico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Masculino , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Rosuvastatina Cálcica , Simvastatina/uso terapéutico , Sulfonamidas/uso terapéuticoRESUMEN
ApoC-III is a proatherogenic protein associated with elevated triglycerides; its deficiency is associated with reduced atherosclerosis. Mixed dyslipidemia, characterized by elevated triglyceride and apoC-III levels and low HDL cholesterol level, with or without elevated LDL cholesterol, increases cardiovascular disease risk and is commonly treated with combined statin and fibrate therapy. We sought to identify single nucleotide polymorphisms (SNPs) associated with apoC-III level response to combination therapy with statins and fenofibric acid (FA) in individuals with mixed dyslipidemia. Participants (n = 1,250) in a multicenter, randomized, double-blind, active-controlled study examining response to FA alone and in combination with statin were genotyped for candidate SNPs. Multivariate linear regression and two-way ANOVA for percent change in apoC-III level were performed. SNPs in the lipoprotein lipase (LPL) gene region, rs1801177 (P = 4.7 × 10(-8)), rs7016529 (P = 1.2 × 10(-6)), and rs249 (P = 4.1 × 10(-5)), were associated with apoC-III response to combination therapy. A haplotype composed of the minor alleles of these SNPs, with 2% population frequency, was associated with an unexpected apoC-III increase in response to statins and FA. This is the first report to show that genetic variation within the LPL gene region can affect the response of apoC-III levels to combined statin and FA therapy.
Asunto(s)
Apolipoproteína C-III/sangre , Dislipidemias/sangre , Dislipidemias/tratamiento farmacológico , Fenofibrato/análogos & derivados , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Dislipidemias/genética , Femenino , Fenofibrato/uso terapéutico , Haplotipos/genética , Humanos , Lipoproteína Lipasa/genética , Masculino , Polimorfismo de Nucleótido Simple , Análisis de Regresión , Triglicéridos/sangreRESUMEN
BACKGROUND: Chromosome 9p21 single nucleotide polymorphisms (SNPs) have been shown to be associated with coronary heart disease in multiple studies. The aim of the present study was to identify whether these SNPs are associated with recurrent myocardial infarction (MI), revascularization, or death in acute coronary syndrome (ACS) patients or in those undergoing coronary artery bypass grafting (CABG). METHODS AND RESULTS: TexGen registry participants with ACS (n=2,067) or CABG (n=1,176) were evaluated, to assess whether 9p21 SNPs (rs1333049, rs2383206, rs10757278, rs10757274) were associated with recurrent MI (primary outcome), recurrent revascularization, or death (secondary outcomes) at approximately 3.2 years of follow-up. Carriers of risk allele (C) for rs1333049 presented at an earlier age (62 vs. 63.5 years in non-carriers, P=0.0004) with more extensive disease (number of vessels with significant stenosis: 1.9 vs. 1.7 in non-carriers, P=0.001) in the ACS group. In adjusted models, the C allele was not associated with recurrent MI (hazard ratio [HR], 1.01; 95% confidence interval [CI]: 0.74-1.38), recurrent revascularization (HR, 0.98; 95%CI: 0.78-1.23), or death (HR, 0.91; 95%CI: 0.69-1.18) in the ACS or CABG groups (recurrent MI: HR, 0.64; 95%CI: 0.40-1.05; recurrent revascularization: HR, 0.98; 95%CI: 0.61-1.55; death: HR, 0.89; 95%CI: 0.61-1.30). Results were similar for the other 3 SNPs. CONCLUSIONS: 9p21 SNPs were not associated with recurrent MI, revascularization, or mortality after ACS or CABG. Individuals with the rs1333049 C allele, however, may present with earlier and more extensive disease.
Asunto(s)
Cromosomas Humanos Par 9 , Enfermedad de la Arteria Coronaria/genética , Infarto del Miocardio/genética , Polimorfismo de Nucleótido Simple , Anciano , Puente de Arteria Coronaria/efectos adversos , Puente de Arteria Coronaria/mortalidad , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/mortalidad , Enfermedad de la Arteria Coronaria/cirugía , Supervivencia sin Enfermedad , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Infarto del Miocardio/mortalidad , Infarto del Miocardio/cirugía , Fenotipo , Modelos de Riesgos Proporcionales , Recurrencia , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Texas , Factores de Tiempo , Resultado del TratamientoRESUMEN
Aortic aneurysm and dissection cause significant morbidity and mortality. There are several known single gene disorders that predispose to isolated aortic disease and eventually aneurysm and dissection. FBN1 mutations are associated with multiple clinical phenotypes, including Marfan syndrome (MFS), MASS phenotype, and familial ectopia lentis, but rarely with isolated aortic aneurysm and dissection. In this report, we describe three patients who presented with primary descending thoracic aortic dissection and who were found to have an FBN1 mutation. None of the patients fulfilled clinical criteria for the diagnosis of MFS, and all had few or none of the skeletal features typical of the condition. Two patients had a history of long-term hypertension, and such a history was suspected in the third patient. These observations suggest that some individuals with FBN1 mutations have significant aortic disease involvement of other systems that is typical of FBN1 mutation-related syndromes. Superimposed risk factors, such as hypertension, may weaken the aortic wall and eventually lead to aortic dissection. Given that the cost continues to decrease, we suggest that diagnostic DNA sequencing for FBN1 mutations in patients with thoracic aortic aneurysms and dissection may be a practical clinical step in evaluating such patients and at-risk family members.
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Aorta Torácica/patología , Aneurisma de la Aorta Torácica/genética , Disección Aórtica/genética , Proteínas de Microfilamentos/genética , Mutación , Adolescente , Adulto , Disección Aórtica/diagnóstico , Aneurisma de la Aorta Torácica/diagnóstico , Análisis Mutacional de ADN , Femenino , Fibrilina-1 , Fibrilinas , Humanos , Hipertensión/patología , Masculino , Persona de Mediana Edad , Fenotipo , Factores de Riesgo , Análisis de Secuencia de ADNRESUMEN
Mitochondrial cytopathies are characterized by a large variability of clinical phenotypes and severity. The 14487T>C mutation in mtDNA has been recently described to be associated with Leigh syndrome. The 12297T>C mutation has been described in isolated dilated cardiomyopathy patients. Here, we report a family with multiple members who harbor both mutations, with only a few individuals who are affected with Leigh syndrome. Mitochondrial whole genome sequencing analysis in the proband's muscle specimen detected two nearly homoplasmic mutations: 14487T>C (M63V in ND6) and 12297T>C in the tRNA (Leu) (CUN) gene. These two mutations were also detected in the blood, urine sediments, hair follicles, and buccal swab samples of all matrilineal relatives tested. All individuals tested were nearly homoplasmic for the 12297T>C mutation, but had variable degrees of heteroplasmy for 14487T>C. We also screened for the frequency of these two mutations. Of 268 patients with Leigh or Leigh-like disease, one case was found to harbor the 14487T>C mutation (0.3%), and one had the 12297T>C mutation (0.3%). Neither mutation was detected in the 88 patients meeting MELAS syndrome criteria nor in the 56 patients with respiratory chain complex I or I+III deficiency. In conclusion, the 14487T>C mutation appears as the primary etiology of Leigh syndrome in this family, demonstrating the high level of heteroplasmy needed for a clinically significant phenotype with this mutation. The 12297T>C mutation was not associated with dilated cardiomyopathy for the family members who were clinically evaluated and who were shown by testing to be nearly homoplasmic for that mutation.
Asunto(s)
ADN Mitocondrial/genética , Enfermedad de Leigh/genética , Mutación , NADH Deshidrogenasa/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Cartilla de ADN , Sondas de ADN , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , NADH Deshidrogenasa/química , Linaje , Reacción en Cadena de la Polimerasa , Homología de Secuencia de AminoácidoRESUMEN
The mitochondrial 13513G>A (D393N) mutation in the ND5 subunit of the respiratory chain complex I was initially described in association with MELAS syndrome. Recent observations have linked this mutation to Leigh disease. We screened for the 13513G>A mutation in a cohort of 265 patients with Leigh and Leigh-like disease. The mutation was found in a total of 5 patients. An additional patient who had clinical presentation consistent with a Leigh-like phenotype but with a normal brain MRI was added to the cohort. None of an additional 88 patients meeting MELAS disease criteria, nor 56 patients with respiratory chain deficiency screened for the 13513G>A were found positive for the mutation. The most frequent clinical manifestations in our patients were hypotonia, ocular and cerebellar involvement. Low mutation heteroplasmy in the range of 20-40% was observed in all 6 patients. This observation is consistent with the previously reported low heteroplasmy of this mutation in some patients with the 13513G>A mutation and complex I deficiency. However, normal complex I activity was observed in two patients in our cohort. As most patients with Leigh-like disease and the 13513G>A mutation have been described with complex I deficiency, this report adds to the previously reported subset of patients with normal respiratory complex function. We conclude that in any patient with Leigh or Leigh-like disease, testing for the 13513G>A mutation is clinically relevant and low mutant loads in blood or muscle may be considered pathogenic, in the presence of normal respiratory chain enzyme activities.
Asunto(s)
Complejo I de Transporte de Electrón/deficiencia , Enfermedad de Leigh/enzimología , Enfermedad de Leigh/genética , Mitocondrias/genética , Proteínas Mitocondriales/deficiencia , Músculos/enzimología , Mutación Puntual , Secuencia de Aminoácidos , Preescolar , Estudios de Cohortes , Análisis Mutacional de ADN , Complejo I de Transporte de Electrón/química , Complejo I de Transporte de Electrón/genética , Femenino , Humanos , Lactante , Masculino , Mitocondrias/química , Mitocondrias/enzimología , Proteínas Mitocondriales/química , Proteínas Mitocondriales/genética , Datos de Secuencia Molecular , Músculos/química , Mutación Missense , Fenotipo , Alineación de SecuenciaRESUMEN
BACKGROUND: With regard to ethnic predilections for Gaucher disease, the most common storage disorder, Ashkenazi Jews are at risk for the non-neuronopathic form (type I), Norbottnian Swedes are at risk for the subacute neuronopathic form (type III), and perhaps Arabs are at risk for the very rare cardiac variant of the subacute neuronopathic form (type IIIc) for which there is a relatively tight genotype-phenotype correlation. Type II, the acute infantile form, being the rarest form, has not been associated with any ethnic predilection. OBJECTIVES: To examine whether Arab ethnicity influences the Gaucher phenotype. METHODS: We reviewed the records of all Arab patients in a referral clinic of 586 patients in Israel. RESULTS: There were 46 patients (7.8%) of Arab ethnicity: 23 (50%) had type I disease, 16 (34.8%) had type IIIc disease, 4 (8.7%) had type IIIb disease, and 3 (6.5%) had type II disease. Type IIIc disease was characterized by genotype-phenotype correlation with homozygosity for the D409H (1342C) mutation. All five Bedouin patients (10.9%) had the R48W (C259T) mutation on at least one allele. CONCLUSIONS: For all genotypes, disease severity among Arab patients was relatively similar to that reported among other Caucasian patients. Apparently Arab ethnicity does not impact phenotypic expression in Gaucher disease in a unique manner. The predilection for type IIIc may be a result of consanguinity.
Asunto(s)
Árabes , Enfermedad de Gaucher/etnología , Adolescente , Adulto , Árabes/genética , Niño , Preescolar , Femenino , Enfermedad de Gaucher/clasificación , Enfermedad de Gaucher/genética , Genotipo , Humanos , Lactante , Israel , Masculino , FenotipoRESUMEN
BACKGROUND: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG). RESULTS: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing. CONCLUSIONS: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.
Asunto(s)
Fascitis Necrotizante/complicaciones , Úlcera por Presión/etiología , Infecciones de los Tejidos Blandos/complicaciones , Antibacterianos/uso terapéutico , Desbridamiento/métodos , Diagnóstico Diferencial , Fascitis Necrotizante/diagnóstico , Fascitis Necrotizante/terapia , Resultado Fatal , Femenino , Humanos , Persona de Mediana Edad , Úlcera por Presión/diagnóstico , Úlcera por Presión/terapia , Infecciones de los Tejidos Blandos/diagnóstico , Infecciones de los Tejidos Blandos/terapiaRESUMEN
Lipoprotein-X, which is composed of phospholipids and non-esterified cholesterol, is an abnormal lipoprotein with a density range similar to LDL-C. The two most common ways which lipoprotein-X accumulates is from reflux of bile salts into plasma or deficiency in lecithin cholesterol acyltransferase. This is a case of severe hypercholesterolemia and liver disease in a 3- year old male that presented with pruritus, pale stool, scleral ictus, and abdominal distention. He was diagnosed with primary sclerosing cholangitis which was confirmed by liver biopsy. Our patient was treated with steroids and immunomodulator therapy which was associated with significant reduction in cholestasis and LDL-C levels. Lipoprotein-X has several properties that make it anti-atherogenic, which raises the question if treatment for hypercholesterolemia should be initiated.