322 research outputs found
Are all the previously reported genetic variants in limb girdle muscular dystrophy genes pathogenic?
No full textHundreds of variants in autosomal genes associated with the limb girdle muscular dystrophies (LGMDs) have been reported as being causative. However, in most cases the proof of pathogenicity derives from their non-occurrence in hundreds of healthy controls and/or from segregation studies in small families. The limited statistics of the genetic variations in the general population may hamper a correct interpretation of the effect of variants on the protein. To clarify the meaning of low-frequency variants in LGMD genes, we have selected all variants described as causative in the Leiden Open Variation Database and the Human Gene Mutation Database. We have systematically searched for their frequency in the NHLBI GO Exome Sequencing Project (ESP) and in our internal database. Surprisingly, the ESP contains about 4% of the variants previously associated with a dominant inheritance and about 9% of those associated with a recessive inheritance. The putative disease alleles are much more frequent than those estimated considering the disease prevalence. In conclusion, we hypothesize that a number of disease-associated variants are non-pathogenic and that other variations are not fully penetrant, even if they affect the protein function, suggesting a more complex genetic mechanisms for such heterogeneous disorders
Prediction of rare single-nucleotide causative mutations for muscular diseases in pooled NGS experiments
No full textPrediction of rare single-nucleotide causative mutations for muscular diseases in pooled next-generation sequencing experiments.
No full textAbstract Next-generation sequencing (NGS) is a new approach for biomedical research, useful for the diagnosis of genetic diseases in extremely heterogeneous conditions. In this work, we describe how data generated by high-throughput NGS experiments can be analyzed to find single nucleotide polymorphisms (SNPs) in DNA samples of patients affected by neuromuscular disorders. In particular, we consider untagged pooled NGS data, where DNA samples of different individuals are combined in a single experiment, still providing information with an uncertainty limited to only two patients. At the moment, only few publications address the problem of SNPs detection in pooled experiments, and existing tools are often inaccurate. We propose a computational procedure consisting of two parts. In the first, data are filtered by means of decision rules. The second phase is based on a supervised classification technique. In the present work, we compare different de facto standard supervised and unsupervised procedures to identify and classify variants potentially related to muscular diseases, and we discuss results in terms of statistical and biological validation
MotorPlex provides accurate variant detection across large muscle genes both in single myopathic patients and in pools of DNA samples
No full textMutations in ~100 genes cause muscle diseases with complex and often unexplained genotype/phenotype correlations. Next-generation sequencing studies identify a greater-than-expected number of genetic variations in the human genome. This suggests that existing clinical monogenic testing systematically miss very relevant information.We have created a core panel of genes that cause all known forms of nonsyndromic muscle disorders (MotorPlex). It comprises 93 loci, among which are the largest and most complex human genes, such as TTN, RYR1, NEB and DMD. MotorPlex captures at least 99.2% of 2,544 exons with a very accurate and uniform coverage. This quality is highlighted by the discovery of 20-30% more variations in comparison with whole exome sequencing. The coverage homogeneity has also made feasible to apply a cost-effective pooled sequencing strategy while maintaining optimal sensitivity and specificity.We studied 177 unresolved cases of myopathies for which the best candidate genes were previously excluded. We have identified known pathogenic variants in 52 patients and potential causative ones in further 56 patients. We have also discovered 23 patients showing multiple true disease-associated variants suggesting complex inheritance. Moreover, we frequently detected other nonsynonymous variants of unknown significance in the largest muscle genes. Cost-effective combinatorial pools of DNA samples were similarly accurate (97-99%). MotorPlex is a very robust platform that overcomes for power, costs, speed, sensitivity and specificity the gene-by-gene strategy. The applicability of pooling makes this tool affordable for the screening of genetic variability of muscle genes also in a larger population. We consider that our strategy can have much broader applications
Nicorandil, a new vasodilator drug, in patients with essential hypertension
No full textIn 12 mild to moderate hypertensive patients we investigated the acute antihypertensive efficacy of three different doses of nicorandil, a new vasodilating agent which probably acts by increasing the potassium efflux from smooth muscle cells and causing a cellular hyperpolarization. After a 3-day placebo period the patients were given, according to a double-blind Latin-square randomized design, 10, 20 and 30 mg nicorandil as a single acute dose every other day. Blood pressure and the heart rate were measured in both supine and upright positions at various times for 24 h after the dosing; fractional urine collections were obtained at the end of the placebo period and after each active dose. All doses of nicorandil similarly and significantly (P less than 0.01) reduced supine blood pressure, with a peak after 4-6 h (10 mg: -21/-8 mmHg; 20 mg: -20/-9 mmHg; 30 mg: -29/-17 mmHg), and the effect was still present, though reduced, after 24 h; no change in the heart rate was observed. The results from the upright position were similar. There were no significant changes in urine volume and electrolyte excretion during the nicorandil administration. The three different doses of nicorandil caused similar acute blood pressure reductions without change in the heart rate, nor in the urine volume and urinary sodium
Nicorandil, a new vasodilator drug, in patients with essential hypertension
No full textIn 12 mild to moderate hypertensive patients we investigated the acute antihypertensive efficacy of three different doses of nicorandil, a new vasodilating agent which probably acts by increasing the potassium efflux from smooth muscle cells and causing a cellular hyperpolarization. After a 3-day placebo period the patients were given, according to a double-blind Latin-square randomized design, 10, 20 and 30 mg nicorandil as a single acute dose every other day. Blood pressure and the heart rate were measured in both supine and upright positions at various times for 24 h after the dosing; fractional urine collections were obtained at the end of the placebo period and after each active dose. All doses of nicorandil similarly and significantly (P less than 0.01) reduced supine blood pressure, with a peak after 4-6 h (10 mg: -21/-8 mmHg; 20 mg: -20/-9 mmHg; 30 mg: -29/-17 mmHg), and the effect was still present, though reduced, after 24 h; no change in the heart rate was observed. The results from the upright position were similar. There were no significant changes in urine volume and electrolyte excretion during the nicorandil administration. The three different doses of nicorandil caused similar acute blood pressure reductions without change in the heart rate, nor in the urine volume and urinary sodium
alpha-Adrenoceptors and age-dependent decrease in plasma renin activity in essential hypertension.
No full text
Antihypertensive and water and sodium balance effects of felodipine, a new vasodilating calcium antagonist, in hypertensive patients
No full textFelodipine, a new dihydropyridine derivative with a selective action on vascular smooth muscle, was investigated in 2 short term studies in hypertensive patients. In the first study, oral administration of felodipine 12.5 mg three times daily in a preliminary tablet formulation for 3 days significantly reduced supine and upright blood pressure with only a slight increase in heart rate and no clinically relevant signs of sodium and water retention. By increasing each dose to 25 and 50 mg three times daily, there was a further, but quite moderate, decrease in blood pressure; however, this was accompanied by an increase in heart rate and a tendency towards a reduction of creatinine clearance and urinary sodium output. In the second study, a new oral formulation containing 10 mg felodipine, administered twice daily for 7 days, was effective in lowering blood pressure without a clinically relevant tachycardia. Following the first dose of felodipine, urinary sodium excretion was slightly increased while potassium excretion showed only minor changes. The new calcium antagonist, felodipine, lowers blood pressure without the clinically relevant adverse reactions commonly related to other direct vasodilator antihypertensive drugs
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