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1. Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients.

Author

Gómez, Juan, Lorca, Rebeca, Reguero, Julian R., Morís, César, Martín, María, Tranche, Salvador, Alonso, Belén, Iglesias, Sara, Alvarez, Victoria, Díaz-Molina, Beatriz, Avanzas, Pablo, and Coto, Eliecer

Abstract

Background--Recent exome sequencing studies identified filamin C (FLNC) as a candidate gene for hypertrophic cardiomyopathy (HCM). Our aim was to determine the rate of FLNC candidate variants in a large cohort of HCM patients who were also sequenced for the main sarcomere genes. Methods and Results--A total of 448 HCM patients were next generation-sequenced (semiconductor chip technology) for the MYH7, MYBPC3, TNNT2, TNNI3, ACTC1, TNNC1, MYL2, MYL3, TPM1, and FLNC genes. We also sequenced 450 healthy controls from the same population. Based on the reported population frequencies, bioinformatic criteria, and familial segregation, we identified 20 FLNC candidate variants (13 new; 1 nonsense; and 19 missense) in 22 patients. Compared with the patients, only 1 of the control's missense variants was nonreported (P=0.007; Fisher exact probability test). Based on the familial segregation and the reported functional studies, 6 of the candidate variants (in 7 patients) were finally classified as likely pathogenic, 10 as variants of uncertain significance, and 4 as likely benign. Conclusions--We provide a compelling evidence of the involvement of FLNC in the development of HCM. Most of the FLNC variants were associated with mild forms of HCM and a reduced penetrance, with few affected in the families to confirm the segregation. Our work, together with others who found FLNC variants among patients with dilated and restrictive cardiomyopathies, pointed to this gene as an important cause of structural cardiomyopathies. [ABSTRACT FROM AUTHOR]

Published
2017
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3. SCN5A Mutation Type and a Genetic Risk Score Associate Variably with Brugada Syndrome Phenotype in SCN5A Families

Author

Peter Lichtner, Thomas Meitinger, Wataru Shimizu, Alison Muir, F. Kyndt, Michael W.T. Tanck, Seiko Ohno, Martina Muggenthaler, Michael J. Ackerman, Vincent Probst, Stephen P. Page, Jean-Jacques Schott, Silvia Castelletti, Hariharan Raju, Jean-Baptiste Gourraud, Joseph Galvin, Taisuke Ishikawa, Eline A. Nannenberg, Dan M. Roden, Doris Škorić-Milosavljević, Kazuhiro Takahashi, Pascal P. McKeown, Federica Dagradi, Lia Crotti, Yanushi D. Wijeyeratne, Julien Barc, Yuka Mizusawa, Peter J. Schwartz, Michael Papadakis, Margherita Torchio, Sanjay Sharma, Velislav N. Batchvarov, Naomasa Makita, Richard Redon, Christian Veltmann, Elijah R. Behr, Takeshi Aiba, Martin Borggrefe, Rafik Tadros, Connie R. Bezzina, J. Martijn Bos, David J. Tester, Isabelle Denjoy, Minoru Horie, Arthur A.M. Wilde, St George's, University of London, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centro Cardiologico Monzino [Milano], Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS)-Dpt di Scienze Cliniche e di Comunità [Milano] (DISCCO), Università degli Studi di Milano [Milano] (UNIMI)-Università degli Studi di Milano [Milano] (UNIMI), Mayo Clinic [Rochester], Belfast Health and Social Care Trust, Hannover Medical School [Hannover] (MHH), University of Shiga Prefecture, National Cerebral and Cardiovascular Center (NCCC - OSAKA), Osaka University [Osaka], Leeds Teaching Hospitals NHS Trust, University of Dublin, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Helmholtz-Zentrum München (HZM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Iwate Prefectural University [Takizawa], Vanderbilt University School of Medicine [Nashville], University of Heidelberg, Medical Faculty, Wijeyeratne, Y, Tanck, M, Mizusawa, Y, Batchvarov, V, Barc, J, Crotti, L, Bos, J, Tester, D, Muir, A, Veltmann, C, Ohno, S, Page, S, Galvin, J, Tadros, R, Muggenthaler, M, Raju, H, Denjoy, I, Schott, J, Gourraud, J, Skoric-Milosavljevic, D, Nannenberg, E, Redon, R, Papadakis, M, Kyndt, F, Dagradi, F, Castelletti, S, Torchio, M, Meitinger, T, Lichtner, P, Ishikawa, T, Wilde, A, Takahashi, K, Sharma, S, Roden, D, Borggrefe, M, Mckeown, P, Shimizu, W, Horie, M, Makita, N, Aiba, T, Ackerman, M, Schwartz, P, Probst, V, Bezzina, C, Behr, E, Unité de recherche de l'institut du thorax (ITX-lab), Dpt di Scienze Cliniche e di Comunità [Milano] (DISCCO), Università degli Studi di Milano = University of Milan (UNIMI)-Università degli Studi di Milano = University of Milan (UNIMI)-Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Helmholtz Zentrum München = German Research Center for Environmental Health, HAL-SU, Gestionnaire, Epidemiology and Data Science, APH - Methodology, Graduate School, ACS - Heart failure & arrhythmias, Amsterdam Reproduction & Development (AR&D), Human Genetics, Cardiology, ACS - Pulmonary hypertension & thrombosis, and ACS - Atherosclerosis & ischemic syndromes

Subjects
genetics, human, congenital, hereditary, and neonatal diseases and abnormalities, Scn5a gene, phenotype, BIO/18 - GENETICA, 030204 cardiovascular system & hematology, risk score, 03 medical and health sciences, 0302 clinical medicine, Brugada Syndrome, Genetics, Human, Penetrance, Phenotype, Risk Score, Medicine, genetics, Brugada syndrome, 030212 general & internal medicine, human, cardiovascular diseases, Genetic risk, penetrance, Genetics, Framingham Risk Score, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, fungi, General Medicine, Original Articles, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, Human genetics, 3. Good health, Brugada ECG Pattern, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, cardiovascular system, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Supplemental Digital Content is available in the text., Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K-SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles). Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45–11.85]; P=0.0078). Among SCN5A-positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89–6.22]; P=0.0846). In SCN5A-negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84–269.30]; P=0.0146). Among E1784K-SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93–13.62]; P=0.0011). Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.

Published
2020
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4. SCN5A mutation type and a genetic risk score associate variably with brugada syndrome phenotype in SCN5A families

Author

Wijeyeratne, Y, Tanck, M, Mizusawa, Y, Batchvarov, V, Barc, J, Crotti, L, Bos, J, Tester, D, Muir, A, Veltmann, C, Ohno, S, Page, S, Galvin, J, Tadros, R, Muggenthaler, M, Raju, H, Denjoy, I, Schott, J, Gourraud, J, Skoric-Milosavljevic, D, Nannenberg, E, Redon, R, Papadakis, M, Kyndt, F, Dagradi, F, Castelletti, S, Torchio, M, Meitinger, T, Lichtner, P, Ishikawa, T, Wilde, A, Takahashi, K, Sharma, S, Roden, D, Borggrefe, M, Mckeown, P, Shimizu, W, Horie, M, Makita, N, Aiba, T, Ackerman, M, Schwartz, P, Probst, V, Bezzina, C, Behr, E, Wijeyeratne Y. D., Tanck M. W., Mizusawa Y., Batchvarov V., Barc J., Crotti L., Bos J. M., Tester D. J., Muir A., Veltmann C., Ohno S., Page S. P., Galvin J., Tadros R., Muggenthaler M., Raju H., Denjoy I., Schott J. -J., Gourraud J. -B., Skoric-Milosavljevic D., Nannenberg E. A., Redon R., Papadakis M., Kyndt F., Dagradi F., Castelletti S., Torchio M., Meitinger T., Lichtner P., Ishikawa T., Wilde A. A. M., Takahashi K., Sharma S., Roden D. M., Borggrefe M. M., McKeown P. P., Shimizu W., Horie M., Makita N., Aiba T., Ackerman M. J., Schwartz P. J., Probst V., Bezzina C. R., Behr E. R., Wijeyeratne, Y, Tanck, M, Mizusawa, Y, Batchvarov, V, Barc, J, Crotti, L, Bos, J, Tester, D, Muir, A, Veltmann, C, Ohno, S, Page, S, Galvin, J, Tadros, R, Muggenthaler, M, Raju, H, Denjoy, I, Schott, J, Gourraud, J, Skoric-Milosavljevic, D, Nannenberg, E, Redon, R, Papadakis, M, Kyndt, F, Dagradi, F, Castelletti, S, Torchio, M, Meitinger, T, Lichtner, P, Ishikawa, T, Wilde, A, Takahashi, K, Sharma, S, Roden, D, Borggrefe, M, Mckeown, P, Shimizu, W, Horie, M, Makita, N, Aiba, T, Ackerman, M, Schwartz, P, Probst, V, Bezzina, C, Behr, E, Wijeyeratne Y. D., Tanck M. W., Mizusawa Y., Batchvarov V., Barc J., Crotti L., Bos J. M., Tester D. J., Muir A., Veltmann C., Ohno S., Page S. P., Galvin J., Tadros R., Muggenthaler M., Raju H., Denjoy I., Schott J. -J., Gourraud J. -B., Skoric-Milosavljevic D., Nannenberg E. A., Redon R., Papadakis M., Kyndt F., Dagradi F., Castelletti S., Torchio M., Meitinger T., Lichtner P., Ishikawa T., Wilde A. A. M., Takahashi K., Sharma S., Roden D. M., Borggrefe M. M., McKeown P. P., Shimizu W., Horie M., Makita N., Aiba T., Ackerman M. J., Schwartz P. J., Probst V., Bezzina C. R., and Behr E. R.

Abstract

Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K-SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles). Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45-11.85]; P=0.0078). Among SCN5A-positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89-6.22]; P=0.0846). In SCN5A-negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84-269.30]; P=0.0146). Among E1784K-SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93-13.62]; P=0.0011). Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.

Published
2020

5. Resistance Artery Creatine Kinase mRNA and Blood Pressure in Humans.

Author

Karamat, Fares A., Oudman, Inge, Ris-Stalpers, Carrie, Afink, Gijs B., Keijser, Remco, Clark, Joseph E., van Montfrans, Gert A., and Brewster, Lizzy M.

Abstract

Hypertension remains the main risk factor for cardiovascular death. Environmental and biological factors are known to contribute to the condition, and circulating creatine kinase was reported to be the main predictor of blood pressure in the general population. This was proposed to be because of high resistance artery creatine kinase-BB rapidly regenerating ATP for vascular contractility. Therefore, we assessed whether creatine kinase isoenzyme mRNA levels in human resistance arteries are associated with blood pressure. We isolated resistance-sized arteries from omental fat donated by consecutive women undergoing uterine fibroid surgery. Blood pressure was measured in the sitting position. Vessels of 13 women were included, 6 normotensive and 7 hypertensive, mean age 42.9 years (SE, 1.6) and mean systolic/ diastolic blood pressure, 144.8 (8.0)/86.5 (4.3) mmHg. Arteriolar creatine kinase isoenzyme mRNA was assessed using quantitative real-time polymerase chain reaction. Normalized creatine kinase B mRNA copy numbers, ranging from 5.2 to 24.4 (mean, 15.0; SE, 1.9), showed a near-perfect correlation with diastolic blood pressure (correlation coefficient, 0.9; 95% confidence interval, 0.6-1.0) and were well correlated with systolic blood pressure, with a 90% relative increase in resistance artery creatine kinase B mRNA in hypertensives compared with normotensives, normalized copy numbers were, respectively, 19.3 (SE, 2.0) versus 10.1 (SE, 2.1), P=0.0045. To our knowledge, this is the first direct evidence suggesting that resistance artery creatine kinase mRNA expression levels concur with blood pressure levels, almost doubling with hypertension. These findings add to the evidence that creatine kinase might be involved in the vasculature's pressor responses. [ABSTRACT FROM AUTHOR]

Published
2014
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6. Pacemakers as Atrial Fibrillation Detectors: Finding Racial Differences and Opportunities for Preventing Stroke

Author

Lippincott Williams Wilkins

Subjects
Male, Pacemaker, Artificial, Time Factors, Epidemiology, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, race and ethnicity, Electrocardiography, 0302 clinical medicine, Risk Factors, Atrial Fibrillation, genetics, 030212 general & internal medicine, Stroke, Aged, 80 and over, Cardiac Pacing, Artificial, Atrial fibrillation, Middle Aged, humanities, Editorial, Atrial Flutter, Cardiovascular Diseases, Cardiology, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, genetics, human, Risk Assessment, White People, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, ischemic stroke, Humans, Intensive care medicine, Aged, Proportional Hazards Models, Retrospective Studies, Fibrillation, business.industry, Editorials, Correction, Anticoagulants, Health Status Disparities, medicine.disease, United States, Black or African American, Ischemic stroke, Racial differences, business
Abstract

Black US residents experience higher rates of ischemic stroke than white residents but have lower rates of clinically apparent atrial fibrillation (AF), a strong risk factor for stroke. It is unclear whether black persons truly have less AF or simply more undiagnosed AF.We obtained administrative claims data from state health agencies regarding all emergency department visits and hospitalizations in California, Florida, and New York. We identified a cohort of patients with pacemakers, the regular interrogation of which reduces the likelihood of undiagnosed AF. We compared rates of documented AF or atrial flutter at follow-up visits using Kaplan-Meier survival statistics and Cox proportional hazards models adjusted for demographic characteristics and vascular risk factors. We identified 10 393 black and 91 380 white patients without documented AF or atrial flutter before or at the index visit for pacemaker implantation. During 3.7 (±1.8) years of follow-up, black patients had a significantly lower rate of AF (21.4%; 95% CI 19.8-23.2) than white patients (25.5%; 95% CI 24.9-26.0). After adjustment for demographic characteristics and comorbidities, black patients had a lower hazard of AF (hazard ratio 0.91; 95% CI 0.86-0.96), a higher hazard of atrial flutter (hazard ratio 1.29; 95% CI 1.11-1.49), and a lower hazard of the composite of AF or atrial flutter (hazard ratio 0.94; 95% CI 0.88-99).In a population-based sample of patients with pacemakers, black patients had a lower rate of AF compared with white patients. These findings indicate that the persistent racial disparities in rates of ischemic stroke are likely to be related to factors other than undiagnosed AF.

Published
2016

7. SCN5A Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in SCN5A Families.

Author

Wijeyeratne YD, Tanck MW, Mizusawa Y, Batchvarov V, Barc J, Crotti L, Bos JM, Tester DJ, Muir A, Veltmann C, Ohno S, Page SP, Galvin J, Tadros R, Muggenthaler M, Raju H, Denjoy I, Schott JJ, Gourraud JB, Skoric-Milosavljevic D, Nannenberg EA, Redon R, Papadakis M, Kyndt F, Dagradi F, Castelletti S, Torchio M, Meitinger T, Lichtner P, Ishikawa T, Wilde AAM, Takahashi K, Sharma S, Roden DM, Borggrefe MM, McKeown PP, Shimizu W, Horie M, Makita N, Aiba T, Ackerman MJ, Schwartz PJ, Probst V, Bezzina CR, and Behr ER

Subjects
Adult, Alleles, Female, Genetic Association Studies, Haploinsufficiency genetics, Humans, Likelihood Functions, Loss of Function Mutation genetics, Male, Phenotype, Risk Factors, Brugada Syndrome genetics, Genetic Predisposition to Disease, Mutation genetics, NAV1.5 Voltage-Gated Sodium Channel genetics
Abstract

Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations., Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles)., Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45-11.85]; P =0.0078). Among SCN5A -positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89-6.22]; P =0.0846). In SCN5A -negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84-269.30]; P =0.0146). Among E1784K- SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93-13.62]; P =0.0011)., Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.

Published
2020
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8. Exome sequencing in suspected monogenic dyslipidemias

Author

Sigrid W. Fouchier, Sekar Kathiresan, James G. Wilson, Marjorie Risman, Benjamin M. Neale, Catherine Boileau, Masa-aki Kawashiri, M. Mahdi Motazacker, Mathilde Varret, John J.P. Kastelein, Daniel J. Rader, G. Kees Hovingh, Clive R. Pullinger, Jorge F. Haller, Maurizio Averna, Stephen S. Rich, Angelo B. Cefalù, Isabelle Ruel, Jacques Genest, Nathan O. Stitziel, Rahul C. Deo, Namrata Gupta, Davide Noto, Deborah A. Nickerson, John P. Kane, Hiroshi Mabuchi, Jean-Pierre Rabès, Stacey Gabriel, Zuhier Awan, Mason W. Freeman, Deborah N. Farlow, Patrizia Tarugi, Atsushi Nohara, Mark J. Daly, Jay Shendure, Gina M. Peloso, Hayato Tada, Masakazu Yamagishi, Marianne Abifadel, Daniel B. Larach, ACS - Amsterdam Cardiovascular Sciences, Human Genetics, Vascular Medicine, Stitziel, N., Peloso, G., Abifadel, M., Cefalu, A., Fouchier, S., Motazacker, M., Tada, H., Larach, D., Awan, Z., Haller, J., Pullinger, C., Varret, M., Rabès, J., Noto, D., Tarugi, P., Kawashiri, M., Nohara, A., Yamagishi, M., Risman, M., Deo, R., Ruel, I., Shendure, J., Nickerson, D., Wilson, J., Rich, S., Gupta, N., Farlow, D., Neale, B., Daly, M., Kane, J., Freeman, M., Genest, J., Rader, D., Mabuchi, H., Kastelein, J., Hovingh, G., Averna, M., Gabriel, S., Boileau, C., and Kathiresan, S.

Subjects
Male, Settore MED/09 - Medicina Interna, Medical Biotechnology, DNA sequencing, exome, exome sequencing, genetics, human, lipids, mendelian genetics, Biology, Cardiorespiratory Medicine and Haematology, Novel gene, Gene mapping, Clinical Research, Genetics, 2.1 Biological and endogenous factors, Humans, genetics, Exome, human, Aetiology, Mendelian disorders, Genetics (clinical), Exome sequencing, Dyslipidemias, Inborn Errors, Human Genome, High-Throughput Nucleotide Sequencing, Atherosclerosis, Metabolism, Cardiovascular System & Hematology, lipids (amino acids, peptides, and proteins), Female, genetic, Cardiology and Cardiovascular Medicine, Metabolism, Inborn Errors
Abstract

Background— Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We used this technique in an attempt to identify novel genes underlying monogenic dyslipidemias. Methods and Results— We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein cholesterol (after candidate gene sequencing excluded known genetic causes for high low-density lipoprotein cholesterol families) or high-density lipoprotein cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual to account for their burden of common genetic variants known to influence lipid levels. In 9 families, we identified likely pathogenic variants in known lipid genes ( ABCA1 , APOB , APOE , LDLR, LIPA , and PCSK9 ); however, we were unable to identify obvious genetic etiologies in the remaining 32 families, despite follow-up analyses. We identified 3 factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease. Conclusions— We identified the genetic basis of disease in 9 of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies.

Published
2013

11. Heredity : a fact that can be tampered with?

Author

Balzan, Rena and rena.balzan@um.edu.mt

Subjects
Genetics, Human, Heredity, Genetics, Mutation (Biology)
Abstract

The characteristics of every living organism are the product of the interaction between heredity and the environment. Heredity supplies the Individual with a set of characteristics which can be modified to a considerable extent by environmental factors. This article explains the process of genetics., N/A

Published
1978

16. [ESSENTIAL TREMOR IN CHILDHOOD].

Author

STUTTE H and WEBER D

Subjects
Child, Humans, Infant, Essential Tremor, Genetics, Medical, Movement Disorders, Tremor
Published
1963

17. HYPOMELANOSIS.

Author

FITZPATRICK TB

Subjects
Humans, Albinism, Anatomy, Black People, Classification, Genetics, Medical, Hypopigmentation, Phenylketonurias, Pigmentation Disorders, Vitiligo
Published
1964
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19. CYTOLOGICAL EVIDENCE FOR CROSSING-OVER IN VITRO IN HUMAN LYMPHOID CELLS.

Author

GERMAN J

Subjects
In Vitro Techniques, Cell Division, Chromosomes, Genetics, Medical, Leukocytes, Lymphocytes, Research, Tissue Culture Techniques
Abstract

In human blood cells dividing in vitro two chromosomes are occasionally found intimately associated in a quadriradial configuration (Qr). A Qr by traditional interpretation is the result of chromatid interchange. Since the configurations in blood cells often are equal and symmetrical and are composed of homologous chromosomes, they are considered cytological evidence that somatic crossing-over may occur in mammalian cells.

Published
1964
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24. ANNULAR PANCREAS CAUSING DUODENAL OBSTRUCTION IN THE NEONATAL PERIOD.

Author

HYATT HW Sr

Subjects
Female, Humans, Infant, Infant, Newborn, Pregnancy, Congenital Abnormalities, Down Syndrome, Duodenal Obstruction, Genetics, Medical, Infant Mortality, Infant, Newborn, Diseases, Jaundice, Jaundice, Neonatal, Pancreas, Pancreatic Diseases, Polyhydramnios, Statistics as Topic, Surgical Procedures, Operative
Published
1964

25. TASTE DISCRIMINATION IN FAMILIAL DYSAUTONOMIA.

Author

SMITH AA and DANCIS J

Subjects
Adolescent, Child, Humans, Autonomic Nervous System Diseases, Dysautonomia, Familial, Genetics, Medical, Histamine, Hydrochloric Acid, Phosphates, Sucrose, Taste
Published
1964

27. PEPTIC ULCER IN CHILDREN IN SWEDEN DURING THE YEARS 1953-1962.

Author

KARLSTROEM F

Subjects
Adolescent, Child, Humans, Infant, Sweden, Body Constitution, Brain Diseases, Duodenal Ulcer, Genetics, Medical, Hormones, Meckel Diverticulum, Peptic Ulcer, Peptic Ulcer Hemorrhage, Peptic Ulcer Perforation, Statistics as Topic, Stomach Ulcer, Surgical Procedures, Operative
Published
1964

28. [ON THE ETIOLOGY AND PATHOGENESIS OF CANCER].

Author

SCHUEMMELFEDER N and GIMMY J

Subjects
Humans, Carcinogens, Cell Biology, Chromosomes, Cytodiagnosis, Genetics, Medical, Neoplasm Metastasis, Neoplasms etiology, Oncogenic Viruses, Radiation Injuries, Transplantation
Published
1964

33. JAUNDICE IN INFANCY.

Author

NEWMAN L

Subjects
Infant, Infant, Newborn, Biopsy, Carbon Tetrachloride Poisoning, Clinical Enzyme Tests, Congenital Abnormalities, Genetics, Medical, Iatrogenic Disease, Jaundice, Jaundice, Neonatal, Jaundice, Obstructive, Liver Cirrhosis, Liver Diseases, Phosphorus, Toxicology
Published
1964

34. PROLONGED SURVIVAL OF A PATIENT WITH SICKLE CELL ANEMIA.

Author

CHARACHE S and RICHARDSON SN

Subjects
Humans, Anemia, Anemia, Sickle Cell, Black People, Blood Cell Count, Blood Chemical Analysis, Blood Viscosity, Chromium Isotopes, Genetics, Medical, Geriatrics, Hematocrit, Hemoglobinometry, Iron Isotopes, Pseudoxanthoma Elasticum, Statistics as Topic, Urine
Published
1964
Full Text
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39. [BISALBUMINEMIA].

Author

UNGARI S and LOPEZ V

Subjects
Child, Humans, Blood Protein Disorders, Blood Protein Electrophoresis, Genetics, Medical, Histiocytosis, Langerhans-Cell, Serum Albumin
Published
1965

40. HOMOCYSTINURIA: METABOLIC STUDIES ON 3 PATIENTS.

Author

BRENTON DP, CUSWORTH DC, and GAULL GE

Subjects
Child, Humans, Amino Acid Metabolism, Inborn Errors, Blood, Genetics, Medical, Homocysteine, Homocystine, Homocystinuria, Intellectual Disability, Metabolism, Methionine, Neomycin, Urine
Published
1965
Full Text
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47. [FAMILIAL LACTOSE INTOLERANCE].

Author

VALLARINO G, GUSMANO R, and BERIO A

Subjects
Child, Humans, Carbohydrate Metabolism, Carbohydrate Metabolism, Inborn Errors, Genetics, Medical, Lactose, Lactose Intolerance
Published
1965

49. THE PREVENTION OF CONGENITAL DEFECTS.

Author

BARNES AC

Subjects
Female, Humans, Infant, Infant, Newborn, Pregnancy, Abnormalities, Drug-Induced, Congenital Abnormalities, Contraception, Delivery, Obstetric, Eugenics, Genetics, Medical, Insemination, Insemination, Artificial, Labor, Obstetric, Placenta Previa, Pre-Eclampsia, Pregnancy Complications, Pregnancy Complications, Cardiovascular, Prenatal Care, Preventive Medicine, Sterilization, Sterilization, Reproductive, Toxicology
Published
1963

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