Publications by authors named "María Brión"

61 Publications

Association of variants in MYH7, MYBPC3 and TNNT2 with sudden cardiac death-related risk factors in Brazilian patients with hypertrophic cardiomyopathy.

Forensic Sci Int Genet 2021 May 3;52:102478. Epub 2021 Feb 3.

School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address:

Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy (LVH) and is one of the major causes of sudden cardiac death (SCD). An exon-targeted gene sequencing strategy was used to investigate the association of functional variants in sarcomeric genes (MYBPC3, MYH7 and TNNT2) with severe LVH and other SCD-related risk factors in Brazilian HCM patients. Clinical data of 55 HCM patients attending a Cardiology Hospital (Sao Paulo city, Brazil) were recorded. Severe LVH, aborted SCD, family history of SCD, syncope, non-sustained ventricular tachycardia and abnormal blood pressure in response to exercise were evaluated as SCD risk factors. Blood samples were obtained for genomic DNA extraction and the exons and untranslated regions of the MYH7, MYBPC3 and TNNT2 were sequenced using Nextera® and MiSEq® reagents. Variants were identified and annotated using in silico tools, and further classified as pathogenic or benign according to the American College of Medical Genetics and Genomics guidelines. Variants with functional effects were identified in MYBPC3 (n = 9), MYH7 (n = 6) and TNNT2 (n = 4). The benign variants MYBPC3 p.Val158Met and TNNT2 p.Lys263Arg were associated with severe LVH (p < 0.05), and the MYH7 p.Val320Met (pathogenic) was associated with family history of SCD (p = 0.037). Increased risk for severe LVH was found in carriers of MYBPC3 Met158 (c.472 A allele, OR = 13.5, 95% CI = 1.80-101.12, p = 0.011) or combined variants (MYBPC3, MYH7 and TNNT2: OR = 12.39, 95% CI = 2.14-60.39, p = 0.004). Carriers of TNNT2 p.Lys263Arg and combined variants had higher values of septum thickness than non-carriers (p < 0.05). Molecular modeling analysis showed that MYBPC3 158Met reduces the interaction of cardiac myosin-binding protein C (cMyBP-C) RASK domain (amino acids Arg215-Ala216-Ser217-Lys218) with tropomyosin. In conclusion, the variants MYBPC3 p.Val158Met, TNNT2 p.Lys263Arg and MYH7 p.Val320Met individually or combined contribute to the risk of sudden cardiac death and other outcomes of hypertrophic cardiomyopathy.
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http://dx.doi.org/10.1016/j.fsigen.2021.102478DOI Listing
May 2021

COVID-19 and treatment guided by biochemical and molecular diagnostic tests to reduce myocardial damage and cardiotoxicity.

Rev Esp Cardiol (Engl Ed) 2020 08 23;73(8):691-693. Epub 2020 May 23.

Centro de Investigación Biomédica en Red Enfermedades Cardiovaculares, CIBERCV, Madrid, Spain; Grupo de Cardiología, Instituto de Investigación Sanitaria, Santiago de Compostela, A Coruña, Spain; Servicio de Cardiología, Hospital Clínico de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.rec.2020.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245328PMC
August 2020

[COVID-19 and treatment guided by biochemical and molecular diagnostic tests to reduce myocardial damage and cardiotoxicity].

Rev Esp Cardiol 2020 Aug 4;73(8):691-693. Epub 2020 May 4.

Centro de Investigación Biomédica en Red Enfermedades Cardiovaculares, CIBERCV, Madrid, España.

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http://dx.doi.org/10.1016/j.recesp.2020.04.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198176PMC
August 2020

Genetic variants of uncertain significance: How to match scientific rigour and standard of proof in sudden cardiac death?

Leg Med (Tokyo) 2020 Apr 23;45:101712. Epub 2020 Apr 23.

Institute of Public Health, Section of Legal Medicine, Catholic University, Rome, Italy. Electronic address:

In many SCD cases, in particular in pediatric age, autopsy can be completely negative and then a post-mortem genetic testing (molecular autopsy) is indicated. In NGS era finding new/rare variants is extremely frequent and, when only variants of unknown significance are found, molecular autopsy fails to find a cause of death. We describe the emblematic case of the sudden death of a 7-year-old girl. We performed a full-body micro-CT analysis, an accurate autopsy, a serum tryptase test and toxicological tests. Since the only macroscopic abnormality we found was a myocardial bridging (length: 1,1 cm, thickness: 0,5 cm) of the left anterior descending coronary artery, a molecular autopsy has been performed. NGS analysis on victim DNA detected rare variants in DPP6, MYH7, SCN2B and NOTCH1 and segregation analysis was then achieved. On the basis of ACMG/AMP (clinical) guidelines, all the found variants were classified as of unknown significance. In other words, both the macroscopic and genetic anomalies we found were of uncertain significance and then the autopsy failed to find the cause of the death. Our case raises three main discussion points: (a) economical, ethical and legal limitations of genetic investigation; (b) risk that genetic testing does not succeed in finding a certain cause of the death; (c) absence of specific guidelines to face the problem of VUS in forensic cases.
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http://dx.doi.org/10.1016/j.legalmed.2020.101712DOI Listing
April 2020

Polygenic risk score as a key factor in cardiovascular clinical prediction models.

Rev Esp Cardiol (Engl Ed) 2020 Aug 17;73(8):608-610. Epub 2020 Feb 17.

Grupo de Medicina Xenómica, Universidad de Santiago de Compostela, Fundación Pública Galega de Medicina Xenómica, CIBERER, Santiago de Compostela, A Coruña, Spain.

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http://dx.doi.org/10.1016/j.rec.2020.01.003DOI Listing
August 2020

Sudden infant death as the most severe phenotype caused by genetic modulation in a family with atrial fibrillation.

Forensic Sci Int Genet 2019 11 31;43:102159. Epub 2019 Aug 31.

Xenética Cardiovascular, Instituto de Investigación Sanitaria de Santiago de Compostela, Spain; Grupo de Medicina Xenómica, Universidade de Santiago de Compostela, Spain; Red de Enfermedades Cardiovasculares (CIBERCV), Spain.

Aims: To assess the functional impact of two combined KCNH2 variants involved in atrial fibrillation, syncope and sudden infant death syndrome.

Methods And Results: Genetic testing of a 4-month old SIDS victim identified a rare missense heterozygous in KCNH2 variant (V483I) and a missense homozygous polymorphism (K897T) which is often described as a genetic modifier. Electrophysiological characterisation of heterologous HERG channels representing two different KCNH2 genotypes within the family, showed significant differences in both voltage and time dependence of activation and inactivation with a global gain-of-function effect of mutant versus wild type channels and, also, differences between both types of recombinant channels.

Conclusions: The rare variant V483I in combination with K897T produces a gain-of-function effect that represents a pathological substrate for atrial fibrillation, syncope and sudden infant death syndrome events in this family. Ascertaining the genotype-phenotype correlation of genetic variants is imperative for the correct assessment of genetic testing and counselling.

Translational Perspective: According to the current guidelines for clinical interpretation of sequence variants, functional studies are an essential tool for the ascertainment of variant pathogenicity. They are especially relevant in the context of sudden infant death syndrome and sudden cardiac death, where individuals cannot be clinically evaluated. The patch-clamp technique is a gold-standard for analysis of the biophysical mechanisms of ion channels.
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http://dx.doi.org/10.1016/j.fsigen.2019.102159DOI Listing
November 2019

Innovative Strategies in Heart Failure: Present and Future.

Arch Med Res 2018 11 31;49(8):558-567. Epub 2018 Dec 31.

Departamento de Cardiología, Hospital Universitario Santiago de Compostela, Santiago de Compostela, España; Instituto para el Desarrollo e Integración de la Salud, Santiago de Compostela, España; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, España. Electronic address:

Heart failure (HF) is a progressively debilitating disease that considerably decreases the life expectancy and quality of life. It has become an important area of focus since it remains one of the most common reasons for admission in patients over the age of 65. Importantly, the incidence of HF has not declined within the past 20 years, but the survival after onset has increased in younger patients and men. This has been in part due to the growing interest in therapies that may decrease morbidity, mortality, along with the substantial health care expenditures associated with the disease. It can be said that over the past 50 years, there have been three distinct eras relating to HF management; a) the non-pharmacologic era, focused its treatments on fluid restriction; b) the pharmacologic era, marked by the increased use of inotropes and diuretics and the discovery of vasodilators, and the posterior discovery of medications relating to neurohormonal pathways; c) the device era, with the discovery, acceptance, and increased use of implantable cardioverter defibrillators, cardiac resynchronization therapy (CRT), and left ventricular assist devices (LVADs) among others. A new forth era could be about to arrive, with the advent of regenerative therapies. In this review article will discuss new therapeutic discoveries as well as provide insight into future therapies.
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http://dx.doi.org/10.1016/j.arcmed.2018.12.011DOI Listing
November 2018

Sudden unexpected death in the young - Value of massive parallel sequencing in postmortem genetic analyses.

Forensic Sci Int 2018 Dec 26;293:70-76. Epub 2018 Oct 26.

Institute of Legal Medicine, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.

Cases of sudden cardiac death (SCD) in young and apparently healthy individuals represent a devastating event in affected families. Hereditary arrhythmia syndromes, which include primary electrical heart disorders as well as cardiomyopathies, are known to contribute to a significant number of these sudden death cases. We performed postmortem genetic analyses in young sudden death cases (aged <45years) by means of a defined gene panel using massive parallel sequencing (MPS). The data were evaluated bioinformatically and detected sequence variants were assessed using common databases and applying in silico prediction tools. In this study, we identified variants with likely pathogenic effect in 6 of 9 sudden unexpected death (SUD) cases. Due to the detection of numerous unknown and unclassified variants, interpretation of the results proved to be challenging. However, by means of an appropriate evaluation of the findings, MPS represents an important tool to support the forensic investigation and implies great progress for relatives of young SCD victims facilitating adequate risk stratification and genetic counseling.
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http://dx.doi.org/10.1016/j.forsciint.2018.09.034DOI Listing
December 2018

A Novel Calsequestrin 2 Deletion Causing Catecholaminergic Polymorphic Ventricular Tachycardia and Sudden Cardiac Death.

Rev Esp Cardiol (Engl Ed) 2019 Aug 20;72(8):681-683. Epub 2018 Aug 20.

Xenética Cardiovascular, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain; Servicio de Cardiología, Hospital Clínico Universitario de Santiago de Compostela-SERGAS, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Santiago de Compostela, A Coruña, Spain; Grupo de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela -Universidade de Santiago de Compostela- Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, A Coruña, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.rec.2018.07.005DOI Listing
August 2019

Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome.

Heart 2017 11 3;103(22):1795-1799. Epub 2017 May 3.

Servei de Cardiologia, Unitat de Marfan, Hospital Universitari, Vall d'Hebron, Universitat Autònoma de Barcelona, CIBERCV, Barcelona, Spain.

Background: The effect of mutation type on the severity of cardiovascular manifestations in patients with Marfan syndrome (MFS) has been reported with disparity results.

Objectives: This study aims to determine the impact of the mutation type on aortic diameters, aortic dilation rates and on cardiovascular events (ie, aortic dissection and cardiovascular mortality).

Methods: MFS patients with a pathogenic mutation followed at two specialised units were included. mutations were classified as being dominant negative (DN; incorporation of non-mutated and mutated fibrillin-1 in the extracellular matrix) or having haploinsufficiency (HI; only incorporation of non-mutated fibrillin-1, thus a decreased amount of fibrillin-1 protein). Aortic diameters and the aortic dilation rate at the level of the aortic root, ascending aorta, arch, descending thoracic aorta and abdominal aorta by echocardiography and clinical endpoints comprising dissection and death were compared between HI and DN patients.

Results: Two hundred and ninety patients with MFS were included: 113 (39%) with an HI- mutation and 177 (61%) with a DN-. At baseline, patients with HI- had a larger aortic root diameter than patients with DN- (HI: 39.3±7.2 mm vs DN: 37.3±6.8 mm, p=0.022), with no differences in age or body surface area. After a mean follow-up of 4.9±2.0 years, aortic root and ascending dilation rates were increased in patients with HI- (HI: 0.57±0.8 vs DN: 0.28±0.5 mm/year, p=0.004 and HI: 0.59±0.9 vs DN: 0.30±0.7 mm/year, p=0.032, respectively). Furthermore, patients with HI- tended to be at increased risk for the combined endpoint of dissection and death compared with patients with DN- (HR: 3.3, 95% CI 1.0 to 11.4, p=0.060).

Conclusions: Patients with an HI mutation had a more severely affected aortic phenotype, with larger aortic root diameters and a more rapid dilation rate, and tended to have an increased risk of death and dissections compared with patients with a DN mutation.
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http://dx.doi.org/10.1136/heartjnl-2016-310631DOI Listing
November 2017

Postmortem genetic testing should be recommended in sudden cardiac death cases due to thoracic aortic dissection.

Int J Legal Med 2017 Sep 8;131(5):1211-1219. Epub 2017 Apr 8.

Xenética de Enfermidades Cardiovasculares e Oftalmolóxicas, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain.

Background: Acute thoracic aortic dissections and ruptures, the main life-threatening complications of the corresponding aneurysms, are an important cause of sudden cardiac death. Despite the usefulness of the molecular diagnosis of these conditions in the clinical setting, the corresponding forensic field remains largely unexplored. The main goal of this study was to explore and validate a new massive parallel sequencing candidate gene​ assay as a diagnostic tool for acute thoracic aortic dissection autopsy cases.

Materials And Methods: Massive parallel sequencing of 22 thoracic aortic disease candidate genes performed in 17 cases of thoracic aortic dissection using AmpliSeq and Ion Proton technologies. Genetic variants were filtered by location, type, and frequency at the Exome Aggregation Consortium and an internal database and further classified based on the American College of Medical Genetics and Genomics (ACMG) recommendations published in 2015. All prioritized results were confirmed by traditional sequencing.

Results: From the total of 10 potentially pathogenic genetic variants identified in 7 out of the 17 initial samples, 2 of them were further classified as pathogenic, 2 as likely pathogenic, 1 as possibly benign, and the remaining 5 as variants of uncertain significance, reaching a molecular autopsy yield of 23%, approximately.

Conclusions: This massive parallel sequencing candidate gene approach proved useful for the molecular autopsy of aortic dissection sudden cardiac death cases and should therefore be progressively incorporated into the forensic field, being especially beneficial for the anticipated diagnosis and risk stratification of any other family member at risk of developing the same condition.
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http://dx.doi.org/10.1007/s00414-017-1583-9DOI Listing
September 2017

The genetic component of bicuspid aortic valve and aortic dilation. An exome-wide association study.

J Mol Cell Cardiol 2017 01 25;102:3-9. Epub 2016 Nov 25.

Servei de Cardiologia, Hospital Universitari Vall d'Hebron, Barcelona, Spain.

Background: Bicuspid aortic valve is the most common cardiovascular congenital malformation affecting 2% of the general population. The incidence of life-threatening complications, the high heritability, and familial clustering rates support the interest in identifying risk or protective genetic factors. The main objective of the present study was to identify population-based genetic variation associated with bicuspid aortic valve and concomitant ascending aortic dilation.

Materials And Methods: A cross-sectional exome-wide association study was conducted in 565 Spanish cases and 484 controls. Single-marker and gene-based association analyses enriched for low frequency and rare genetic variants were performed on this discovery stage cohort and for the subsets of cases with and without ascending aortic dilation. Discovery-stage association signals and additional markers indirectly associated with bicuspid aortic valve, were genotyped in a replication cohort that comprised 895 Caucasian cases and 1483 controls.

Results: Although none of the association signals were consistent across series, the involvement of HMCN2 in calcium metabolism and valve degeneration caused by calcium deposit, and a nominal but not genome-wide significant association, supported it as an interesting gene for follow-up studies on the genetic susceptibility to bicuspid aortic valve.

Conclusions: The absence of a genome-wide significant association signal shows this valvular malformation may be more genetically complex than previously believed. Exhaustive phenotypic characterization, even larger datasets, and collaborative efforts are needed to detect the combination of rare variants conferring risk which, along with specific environmental factors, could be causing the development of this disease.
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http://dx.doi.org/10.1016/j.yjmcc.2016.11.012DOI Listing
January 2017

ABCC3 Polymorphisms and mRNA Expression Influence the Concentration of a Carboxylic Acid Metabolite in Patients on Clopidogrel and Aspirin Therapy.

Basic Clin Pharmacol Toxicol 2017 May 16;120(5):466-474. Epub 2017 Jan 16.

School of Pharmaceutical Science, University of Sao Paulo, Sao Paulo, Brazil.

Acetylsalicylic acid (ASA) and clopidogrel combined therapy has been reported to be beneficial in patients with acute coronary syndrome (ACS). Antiplatelet drug resistance, especially to clopidogrel, is a multifactorial phenomenon that affects a large number of ACS patients. The genetic contribution to this drug response is not fully elucidated. We investigated the relationship of ABC-type efflux subfamily C member 3 (ABCC3) polymorphisms and mRNA expression with plasma concentrations of clopidogrel, salicylic acid (SA) and a carboxylic acid metabolite (CAM). Clopidogrel, CAM and SA plasma concentrations were measured simultaneously by liquid chromatography-tandem mass spectrometry (LCMS/MS) from 83 ACS patients undergoing percutaneous coronary intervention. ABCC3 (rs757421, rs733392 and rs739923) and CYP2C19*2 (rs4244285) polymorphisms as well as mRNA expression were evaluated. A positive correlation was found between CAM concentrations and ABCC3 mRNA expression (r = 0.494, p < 0.0001). Patients carrying genotype AA (rs757421 variant) had higher CAM concentrations and ABCC3 mRNA expression as compared to those of GG + GA carriers (p = 0.017). A multiple linear regression analysis revealed that ABCC3 mRNA expression (p = 0.017), rs757421 AA genotype (p = 0.001), blood collection time (p = 0.018) and clopidogrel dose (p = 0.001) contributed to the concentration of CAM. No associations were observed for the CYP2C19*2 polymorphism. These results suggest that up-regulation of ABCC3 mRNA expression leads to increased plasma CAM levels through MRP3-mediated cell efflux. The ABCC3 rs757421 polymorphism may contribute to gene expression. Therefore, ABCC3 may be a potential biomarker for the response to clopidogrel.
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http://dx.doi.org/10.1111/bcpt.12703DOI Listing
May 2017

Medico-legal perspectives on sudden cardiac death in young athletes.

Int J Legal Med 2017 Mar 21;131(2):393-409. Epub 2016 Sep 21.

Cardiovascular Genetics Center, Gencardio Institut d'Investigacions Biomèdiques de Girona (IDIBGI), Girona, Spain.

Sudden cardiac death (SCD) in a young athlete represents a dramatic event, and an increasing number of medico-legal cases have addressed this topic. In addition to representing an ethical and medico-legal responsibility, prevention of SCD is directly correlated with accurate eligibility/disqualification decisions, with an inappropriate pronouncement in either direction potentially leading to legal controversy. This review summarizes the common causes of SCD in young athletes, divided into structural (hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, congenital coronary artery anomalies, etc.), electrical (Brugada, congenital LQT, Wolf-Parkinson-White syndrome, etc.), and acquired cardiac abnormalities (myocarditis, etc.). In addition, the roles of hereditary cardiac anomalies in SCD in athletes and the effects of a positive result on them and their families are discussed. The medico-legal relevance of pre-participation screening is analyzed, and recommendations from the American Heart Association and European Society of Cardiology are compared. Finally, the main issues concerning the differentiation between physiologic cardiac adaptation in athletes and pathologic findings and, thereby, definition of the so-called gray zone, which is based on exact knowledge of the mechanism of cardiac remodeling including structural or functional adaptions, will be addressed.
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http://dx.doi.org/10.1007/s00414-016-1452-yDOI Listing
March 2017

PRKG1 and genetic diagnosis of early-onset thoracic aortic disease.

Eur J Clin Invest 2016 Sep 18;46(9):787-94. Epub 2016 Aug 18.

Xenética de Enfermidades Cardiovasculares e Oftalmolóxicas, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain.

Background: The 20% of thoracic aortic aneurysms and dissections independent from the main connective tissue syndromes and expected to be familial has gained importance over the past years. The more frequent pattern of inheritance of these nonsyndromic cases is autosomal dominant with incomplete penetrance and variable expression. Although many candidate genes exist, unresolved familial cases suggest still unravelled genetic variation. The main purpose of this study was to establish the genetic diagnosis of one of those.

Materials And Methods: To begin with, we applied a candidate gene approach based on both traditional and a customized massive parallel sequencing panel, followed by Illumina HiSeq 2000 whole exome sequencing of four family members affected by early-onset thoracic aortic disease and two unaffected relatives. We prioritized whole exome sequencing results based on variant location, type and frequency in general population databases and performed segregation analysis in 14 family members using traditional sequencing.

Results: After the negative results we obtained with candidate gene approaches, the analysis and prioritization of whole exome sequencing results brought out the heterozygote c.530G>A:p.Arg177Gln PRKG1 variant (NM_001098512), located in one of the aortic smooth muscle cell contractile apparatus genes. This candidate variant segregated with thoracic aortic disease, as it was present in seven affected and absent in five unaffected family members, further supporting its causality.

Conclusions: This was the second time PRKG1 was associated with thoracic aortic disease, highlighting and reaffirming it as a strong candidate for gene-based diagnosis of nonsyndromic early-onset cases.
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http://dx.doi.org/10.1111/eci.12662DOI Listing
September 2016

Prospective and Retrospective Diagnosis of Barth Syndrome Aided by Next-Generation Sequencing.

Am J Clin Pathol 2016 Apr 22;145(4):507-13. Epub 2016 Apr 22.

Neonatal Unit, Department of Pediatrics.

Objectives: To establish a genetic and clinical diagnosis in a newborn with fetal-onset dilated cardiomyopathy using next-generation sequencing technologies.

Methods: We have conducted the clinical evaluation of the proband and the molecular characterization of his disease by means of whole-exome sequencing. In addition, the clinical evaluation and subsequent genetic screening of five relatives has been performed. This comprises two males with features of left ventricular noncompaction cardiomyopathy, two females suspected of being carriers, and one pregnant female at risk of being a carrier and thereby transmitting the disease to her child.

Results: We have discovered a novel variant in the TAZ gene by means of whole-exome sequencing. This, together with the performance of further clinical analyses, led to an early diagnosis of Barth syndrome in the proband. The genetic screening of the subject's familial group revealed full cosegregation of the variant with another two affected males and identified several female carriers.

Conclusions: The investigation for Barth syndrome must be considered in male babies and young boys with dilated cardiomyopathy and left ventricular noncompaction. Next-generation sequencing technologies provide an accurate and rapid diagnostic tool in prospectively and retrospectively identifying individuals with this Mendelian syndrome.
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http://dx.doi.org/10.1093/ajcp/aqw025DOI Listing
April 2016

Broad-based molecular autopsy: a potential tool to investigate the involvement of subtle cardiac conditions in sudden unexpected death in infancy and early childhood.

Arch Dis Child 2015 Oct 13;100(10):952-6. Epub 2015 Aug 13.

Xenética de Enfermidades Cardiovasculares, Instituto de Investigación Sanitaria de Santiago, Red de Investigación Cardiovascular (RIC), Santiago De Compostela, Spain Grupo de Medicina Xenómica, University of Santiago de Compostela, Santiago de Compostela, Spain Fundación Pública Galega de Medicina Xenómica, SERGAS, Santiago de Compostela, Spain.

Objectives: Sudden unexplained death in children is a tragic and traumatic event, often worsened when the cause of death cannot be determined. This work aimed to investigate the presence of putative pathogenic genetic variants in a broad spectrum of cardiomyopathy, channelopathy and aortic disease associated genes that may have increased these children's vulnerability to sudden cardiac death.

Design: We performed molecular autopsy of 41 cases of sudden unexplained death in infants and children through massive parallel sequencing of up to 86 sudden cardiac death-related genes. Multiple in silico analyses were conducted together with a thorough review of the literature in order to prioritise the putative pathogenic variants.

Results: A total of 63 variants in 35 cases were validated. The largest proportion of these variants is located within cardiomyopathy genes although this would have been more expected of channelopathy gene variants. Subtle microscopic features of heart tissue may indicate the presence of an early onset cardiomyopathy as a predisposing condition to sudden unexpected death in some individuals.

Conclusions: Next-generation sequencing technologies reveal the existence of a wide spectrum of rare and novel genetic variants in sarcomere genes, compared with that of cardiac ion channels, in sudden unexplained death in infants and children. Our findings encourage further investigation of the role of early onset inherited cardiomyopathies and other diseases involving myocardial dysfunction in these deaths. Early detection of variants in these individuals could help to unmask subtle forms of disease within their relatives, who would eventually benefit from better counselling about their genetic history.
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http://dx.doi.org/10.1136/archdischild-2015-308200DOI Listing
October 2015

Genetic Analysis of Arrhythmogenic Diseases in the Era of NGS: The Complexity of Clinical Decision-Making in Brugada Syndrome.

PLoS One 2015 31;10(7):e0133037. Epub 2015 Jul 31.

Cardiovascular Genetics Center, IdIBGi-Universitat de Girona, Girona, Spain.

Background: The use of next-generation sequencing enables a rapid analysis of many genes associated with sudden cardiac death in diseases like Brugada Syndrome. Genetic variation is identified and associated with 30-35% of cases of Brugada Syndrome, with nearly 20-25% attributable to variants in SCN5A, meaning many cases remain undiagnosed genetically. To evaluate the role of genetic variants in arrhythmogenic diseases and the utility of next-generation sequencing, we applied this technology to resequence 28 main genes associated with arrhythmogenic disorders.

Materials And Methods: A cohort of 45 clinically diagnosed Brugada Syndrome patients classified as SCN5A-negative was analyzed using next generation sequencing. Twenty-eight genes were resequenced: AKAP9, ANK2, CACNA1C, CACNB2, CASQ2, CAV3, DSC2, DSG2, DSP, GPD1L, HCN4, JUP, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ5, KCNQ1, NOS1AP, PKP2, RYR2, SCN1B, SCN3B, SCN4B, SCN5A, SNTA1, and TMEM43. A total of 85 clinically evaluated relatives were also genetically analyzed to ascertain familial segregation.

Results And Discussion: Twenty-two patients carried 30 rare genetic variants in 12 genes, only 4 of which were previously associated with Brugada Syndrome. Neither insertion/deletion nor copy number variation were detected. We identified genetic variants in novel candidate genes potentially associated to Brugada Syndrome. These include: 4 genetic variations in AKAP9 including a de novo genetic variation in 3 positive cases; 5 genetic variations in ANK2 detected in 4 cases; variations in KCNJ2 together with CASQ2 in 1 case; genetic variations in RYR2, including a de novo genetic variation and desmosomal proteins encoding genes including DSG2, DSP and JUP, detected in 3 of the cases. Larger gene panels or whole exome sequencing should be considered to identify novel genes associated to Brugada Syndrome. However, application of approaches such as whole exome sequencing would difficult the interpretation for clinical purposes due to the large amount of data generated. The identification of these genetic variants opens new perspectives on the implications of genetic background in the arrhythmogenic substrate for research purposes.

Conclusions: As a paradigm for other arrhythmogenic diseases and for unexplained sudden death, our data show that clinical genetic diagnosis is justified in a family perspective for confirmation of genetic causality. In the era of personalized medicine using high-throughput tools, clinical decision-making is increasingly complex.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133037PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521779PMC
May 2016

Resequencing and association analysis of coding regions at twenty candidate genes suggest a role for rare risk variation at AKAP9 and protective variation at NRXN1 in schizophrenia susceptibility.

J Psychiatr Res 2015 Jul-Aug;66-67:38-44. Epub 2015 Apr 22.

Instituto de Investigación Sanitaria (IDIS) de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain. Electronic address:

A fraction of genetic risk to develop schizophrenia may be due to low-frequency variants. This multistep study attempted to find low-frequency variants of high effect at coding regions of eleven schizophrenia susceptibility genes supported by genome-wide association studies (GWAS) and nine genes for the DISC1 interactome, a susceptibility gene-set. During the discovery step, a total of 125 kb per sample were resequenced in 153 schizophrenia patients and 153 controls from Galicia (NW Spain), and the cumulative role of low-frequency variants at a gene or at the DISC1 gene-set were analyzed by burden and variance-based tests. Relevant results were meta-analyzed when appropriate data were available. In addition, case-only putative damaging variants were genotyped in a further 419 cases and 398 controls. The discovery step revealed a protective effect of rare missense variants at NRXN1, a result supported by meta-analysis (OR = 0.67, 95% CI: 0.47-0.94, P = 0.021, based on 3848 patients and 3896 controls from six studies). The follow-up step based on case-only putative damaging variants revealed a promising risk variant at AKAP9. This variant, K873R, reached nominal significance after inclusion of 240 additional Spanish controls from databases. The variant, located in an ADCY2 binding region, is absent from large public databases. Interestingly, GWAS revealed an association between common ADCY2 variants and bipolar disorder, a disorder with considerable genetic overlap with schizophrenia. These data suggest a role of rare missense variants at NRXN1 and AKAP9 in schizophrenia susceptibility, probably related to alteration of the excitatory/inhibitory synaptic balance, deserving further investigation.
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http://dx.doi.org/10.1016/j.jpsychires.2015.04.013DOI Listing
February 2016

The relationship between surname frequency and Y chromosome variation in Spain.

Eur J Hum Genet 2016 Jan 22;24(1):120-8. Epub 2015 Apr 22.

Human Evolutionary Genetics Group, Department of Zoology, University of Oxford, Oxford, UK.

In most societies, surnames are passed down from fathers to sons, just like the Y chromosome. It follows that, theoretically, men sharing the same surnames would also be expected to share related Y chromosomes. Previous investigations have explored such relationships, but so far, the only detailed studies that have been conducted are on samples from the British Isles. In order to provide additional insights into the correlation between surnames and Y chromosomes, we focused on the Spanish population by analysing Y chromosomes from 2121 male volunteers representing 37 surnames. The results suggest that the degree of coancestry within Spanish surnames is highly dependent on surname frequency, in overall agreement with British but not Irish surname studies. Furthermore, a reanalysis of comparative data for all three populations showed that Irish surnames have much greater and older surname descent clusters than Spanish and British ones, suggesting that Irish surnames may have considerably earlier origins than Spanish or British ones. Overall, despite closer geographical ties between Ireland and Britain, our analysis points to substantial similarities in surname origin and development between Britain and Spain, while possibly hinting at unique demographic or social events shaping Irish surname foundation and development.
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http://dx.doi.org/10.1038/ejhg.2015.75DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795233PMC
January 2016

Association between SNPs of Metalloproteinases and Prostaglandin F2α Receptor Genes and Latanoprost Response in Open-Angle Glaucoma.

Ophthalmology 2015 May 19;122(5):1040-8.e4. Epub 2015 Feb 19.

Instituto de Oftalmobiologia Aplicada, IOBA, Universidad de Valladolid, Valladolid, Spain; Hospital Clinico Universitario de Valladolid, Valladolid, Spain.

Purpose: To determine whether single nucleotide polymorphisms (SNPs) of genes coding for matrix metalloproteinases (MMPs) and the prostaglandin F2α receptor gene (PTGFR) are related to a response to latanoprost in a white Spanish population of glaucomatous patients.

Design: Case-control study.

Participants: One hundred twenty-four patients with open-angle glaucoma.

Methods: Genotyping was performed in 117 patients with primary open-angle glaucoma with a minimum treatment duration of 4 weeks. Candidate genes and individual polymorphisms were selected according to the effect on the mechanism of action of latanoprost. Multi-SNP haplotype analyses for associations also were tested.

Main Outcome Measures: Diurnal intraocular pressure reduction and genotyping of the SNPs in the MMPs and PTGFR.

Results: The PTGFR SNPs were associated with positive (rs6686438, rs10786455) and negative (rs3753380, rs6672484, rs11578155) responses to latanoprost. Multiple testing found 2 genes, PTGFR and MMP-1, were related to refractoriness to latanoprost.

Conclusions: The SNPs of the PTGFR and MMP-1 genes may determine the latanoprost response in a white European Spanish population. This study identified 5 SNPs related to the latanoprost response; 1 SNP, rs3753380, already has been associated with a poor response to latanoprost in a healthy Japanese population. Latanoprost is a commonly used antiglaucomatous drug, and increased knowledge of its mechanism of action will lead to advances in pharmacogenetics.
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http://dx.doi.org/10.1016/j.ophtha.2014.12.038DOI Listing
May 2015

Predicting proliferative vitreoretinopathy: temporal and external validation of models based on genetic and clinical variables.

Br J Ophthalmol 2015 Jan 29;99(1):41-8. Epub 2014 Jul 29.

Medicina Xenómica, Complexo Hospitalario Universitario de Santiago, IDIS, Santiago de Compostela, Spain University of Santiago de Compostela, Galician Public Foundation for Genomic Medicine, CIBERER, Santiago de Compostela, Spain.

Purpose: To validate three models for predicting proliferative vitreoretinopathy (PVR) based on the analysis of genotypic data and relevant clinical characteristics.

Methods: The validation series consisted of data from 546 patients operated on from primary rhegmatogenous retinal detachment (RRD) coming from centres in the Netherlands, Portugal, Spain and the UK. Temporal and geographical validation was performed. The discrimination capability of each model was analysed and compared with the original series, using a receiver operating curve. Then, clinical variables were combined in order to improve the predictive capability. A risk reclassification analysis was performed with and without each one of the variables. Reclassification of patients was compared and models were readjusted in the original series. Readjusted models were further validated.

Results: One of the models showed good predictability in the temporal sample as well as in the original series (area under the curve (AUC) original=0.7352; AUC temporal=0.6457, 95% CI 50.17 to 78.97). When clinical variables were included, only pre-existent PVR improves the predictability of this model in the validation series (temporal and geographical samples) (AUC original=0.7940 vs AUC temporal=0.7744 and AUC geographical=0.7152). The other models showed acceptable AUC values when clinical variables were included although they were less accurate than in the original series.

Conclusions: Genetic profiling of patients with RRD can improve the predictability of PVR in addition to the well-known clinical biomarkers. This validated formula could be a new tool in our current clinical practice in order to identify those patients at high risk of developing PVR.
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http://dx.doi.org/10.1136/bjophthalmol-2014-305263DOI Listing
January 2015

Whole exome sequencing for the identification of a new mutation in TGFB2 involved in a familial case of non-syndromic aortic disease.

Clin Chim Acta 2014 Nov 19;437:88-92. Epub 2014 Jul 19.

Xenética de enfermidades cardiovasculares e oftalmolóxicas, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain; Grupo de Medicina Xenómica IDIS-USC, Fundación Pública Galega de Medicina Xenómica, 15706 Santiago de Compostela, A Coruña, Spain. Electronic address:

Background: Non-syndromic aortic disease (NSAD) is a frequently asymptomatic but potentially lethal disease characterised by familial cases of thoracic aortic aneurysms and dissections. This monogenic but genetically heterogeneous condition is primarily inherited as an autosomal dominant disorder with low penetrance and variable expression. Mutations in ACTA2, TGFBR1, TGFBR2, MYH11, SMAD3, MYLK, and FBN1 genes have been described but still, there are many unresolved familial cases.

Methods: The whole exome of two distantly related and affected members of a Spanish family with multiple cases of NSAD was analysed through 5500 SOLiD(™) System for the identification of shared and putative pathogenic variants.

Results: A new mutation termed c.C1042T:p.R348C (NM_001135599.2) was identified in TGFB2, a gene located in an evolutionary highly conserved region (Chr1: 218,519,577-218,617,961) that has been recently connected to this disease. The analysis of other family members using capillary sequencing confirmed cosegregation of the mutation with the disease and its incomplete penetrance.

Conclusions: The repeated implication of TGFB2 in the development of thoracic aortic aneurysms and dissections suggests that this gene should be considered during genetic diagnosis of this disease. An accurate diagnosis of affected individuals and additional family members at risk allows for a personalised and more efficient gene-based follow-up and treatment. Finally, the reiterative presence of common musculoskeletal and craniofacial additional features in patients with TGFB2 mutations suggests the existence of a new yet undefined connective tissue syndrome responsible for not only aortic dilation, but also for the other extracardiac alterations present in the affected patients.
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http://dx.doi.org/10.1016/j.cca.2014.07.016DOI Listing
November 2014

Next generation sequencing challenges in the analysis of cardiac sudden death due to arrhythmogenic disorders.

Electrophoresis 2014 Nov 6;35(21-22):3111-6. Epub 2014 Aug 6.

Grupo de Xenética de enfermidades cardiovasculares e oftalmolóxicas, IDIS, RIC Santiago de Compostela, Spain; Fundación Pública Galega de Medicina Xenómica, SERGAS, Santiago de Compostela, Spain.

Inherited arrhythmogenic disorders is a relatively common cause of cardiac sudden death in young people. Diagnosis has been difficult so far due to the genetic heterogeneity of the disease. Next generation sequencing (NGS) is offering a new scenario for diagnosis. The purpose of our study was to validate NGS for the analysis of twenty-eight genes known to be associated with inherited arrhythmogenic disorders and therefore with sudden cardiac death. SureSelect hybridization was used to enrich DNA from 53 samples, prior to be sequenced with the SOLID™ System of Life Technologies. Depth of coverage, consistency of coverage across samples, and location of variants identified were assessed. All the samples showed a depth of coverage over 200×, except one of them discarded because of its coverage below 30×. Average percentage of target bp covered at least 20× was 96.45%. In the remaining samples, following a prioritization process 46 possible variants in 31 samples were found, of which 45 were confirmed by Sanger sequencing. After filtering variants according to their minor allele frequency in the Exome Sequencing Project 27 putative pathogenic variants in 20 samples remained. With the use of in silico tools, 13 variants in 11 samples were classified as likely pathogenic. In conclusion, NGS allowed us to accurately detect arrhythmogenic disease causing mutations in a fast and cost-efficient manner that is suitable for daily clinical and forensic practice of genetic testing of this type of disorders.
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http://dx.doi.org/10.1002/elps.201400148DOI Listing
November 2014

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

Authors:
Dan E Arking Sara L Pulit Lia Crotti Pim van der Harst Patricia B Munroe Tamara T Koopmann Nona Sotoodehnia Elizabeth J Rossin Michael Morley Xinchen Wang Andrew D Johnson Alicia Lundby Daníel F Gudbjartsson Peter A Noseworthy Mark Eijgelsheim Yuki Bradford Kirill V Tarasov Marcus Dörr Martina Müller-Nurasyid Annukka M Lahtinen Ilja M Nolte Albert Vernon Smith Joshua C Bis Aaron Isaacs Stephen J Newhouse Daniel S Evans Wendy S Post Daryl Waggott Leo-Pekka Lyytikäinen Andrew A Hicks Lewin Eisele David Ellinghaus Caroline Hayward Pau Navarro Sheila Ulivi Toshiko Tanaka David J Tester Stéphanie Chatel Stefan Gustafsson Meena Kumari Richard W Morris Åsa T Naluai Sandosh Padmanabhan Alexander Kluttig Bernhard Strohmer Andrie G Panayiotou Maria Torres Michael Knoflach Jaroslav A Hubacek Kamil Slowikowski Soumya Raychaudhuri Runjun D Kumar Tamara B Harris Lenore J Launer Alan R Shuldiner Alvaro Alonso Joel S Bader Georg Ehret Hailiang Huang W H Linda Kao James B Strait Peter W Macfarlane Morris Brown Mark J Caulfield Nilesh J Samani Florian Kronenberg Johann Willeit J Gustav Smith Karin H Greiser Henriette Meyer Zu Schwabedissen Karl Werdan Massimo Carella Leopoldo Zelante Susan R Heckbert Bruce M Psaty Jerome I Rotter Ivana Kolcic Ozren Polašek Alan F Wright Maura Griffin Mark J Daly David O Arnar Hilma Hólm Unnur Thorsteinsdottir Joshua C Denny Dan M Roden Rebecca L Zuvich Valur Emilsson Andrew S Plump Martin G Larson Christopher J O'Donnell Xiaoyan Yin Marco Bobbo Adamo P D'Adamo Annamaria Iorio Gianfranco Sinagra Angel Carracedo Steven R Cummings Michael A Nalls Antti Jula Kimmo K Kontula Annukka Marjamaa Lasse Oikarinen Markus Perola Kimmo Porthan Raimund Erbel Per Hoffmann Karl-Heinz Jöckel Hagen Kälsch Markus M Nöthen Marcel den Hoed Ruth J F Loos Dag S Thelle Christian Gieger Thomas Meitinger Siegfried Perz Annette Peters Hanna Prucha Moritz F Sinner Melanie Waldenberger Rudolf A de Boer Lude Franke Pieter A van der Vleuten Britt Maria Beckmann Eimo Martens Abdennasser Bardai Nynke Hofman Arthur A M Wilde Elijah R Behr Chrysoula Dalageorgou John R Giudicessi Argelia Medeiros-Domingo Julien Barc Florence Kyndt Vincent Probst Alice Ghidoni Roberto Insolia Robert M Hamilton Stephen W Scherer Jeffrey Brandimarto Kenneth Margulies Christine E Moravec Fabiola del Greco M Christian Fuchsberger Jeffrey R O'Connell Wai K Lee Graham C M Watt Harry Campbell Sarah H Wild Nour E El Mokhtari Norbert Frey Folkert W Asselbergs Irene Mateo Leach Gerjan Navis Maarten P van den Berg Dirk J van Veldhuisen Manolis Kellis Bouwe P Krijthe Oscar H Franco Albert Hofman Jan A Kors André G Uitterlinden Jacqueline C M Witteman Lyudmyla Kedenko Claudia Lamina Ben A Oostra Gonçalo R Abecasis Edward G Lakatta Antonella Mulas Marco Orrú David Schlessinger Manuela Uda Marcello R P Markus Uwe Völker Harold Snieder Timothy D Spector Johan Ärnlöv Lars Lind Johan Sundström Ann-Christine Syvänen Mika Kivimaki Mika Kähönen Nina Mononen Olli T Raitakari Jorma S Viikari Vera Adamkova Stefan Kiechl Maria Brion Andrew N Nicolaides Bernhard Paulweber Johannes Haerting Anna F Dominiczak Fredrik Nyberg Peter H Whincup Aroon D Hingorani Jean-Jacques Schott Connie R Bezzina Erik Ingelsson Luigi Ferrucci Paolo Gasparini James F Wilson Igor Rudan Andre Franke Thomas W Mühleisen Peter P Pramstaller Terho J Lehtimäki Andrew D Paterson Afshin Parsa Yongmei Liu Cornelia M van Duijn David S Siscovick Vilmundur Gudnason Yalda Jamshidi Veikko Salomaa Stephan B Felix Serena Sanna Marylyn D Ritchie Bruno H Stricker Kari Stefansson Laurie A Boyer Thomas P Cappola Jesper V Olsen Kasper Lage Peter J Schwartz Stefan Kääb Aravinda Chakravarti Michael J Ackerman Arne Pfeufer Paul I W de Bakker Christopher Newton-Cheh

Nat Genet 2014 Aug 22;46(8):826-36. Epub 2014 Jun 22.

1] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Harvard Medical School, Boston, Massachusetts, USA. [4] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [5].

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
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http://dx.doi.org/10.1038/ng.3014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124521PMC
August 2014

Involvement of LCA5 in Leber congenital amaurosis and retinitis pigmentosa in the Spanish population.

Ophthalmology 2014 Jan 18;121(1):399-407. Epub 2013 Oct 18.

Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain. Electronic address:

Objective: We aimed to identify novel genetic defects in the LCA5 gene underlying Leber congenital amaurosis (LCA) in the Spanish population and to describe the associated phenotype.

Design: Case series.

Participants: A cohort of 217 unrelated Spanish families affected by autosomal recessive or isolated retinal dystrophy, that is, 79 families with LCA and 138 families with early-onset retinitis pigmentosa (EORP). A total of 100 healthy, unrelated Spanish individuals were screened as controls.

Methods: High-resolution homozygosity mapping was performed in 44 patients with LCA using genome-wide single nucleotide polymorphism (SNP) microarrays. Direct sequencing of the LCA5 gene was performed in 5 patients who showed homozygous regions at chromosome 6 and in 173 unrelated individuals with LCA or EORP. The ophthalmic history of 8 patients carrying LCA5 mutations was reviewed and additional examinations were performed, including electroretinography (ERG), optical coherence tomography (OCT), and fundus photography.

Main Outcome Measures: Single nucleotide polymorphism genotyping, identity-by-descent (IBD) regions, LCA5 mutations, best-corrected visual acuity, visual field assessments, fundus appearance, ERG, and OCT findings.

Results: Four novel and 2 previously reported LCA5 mutations have been identified in 6 unrelated families with LCA by homozygosity mapping or Sanger sequencing. Thus, LCA5 mutations have a frequency of 7.6% in the Spanish population. However, no LCA5 mutations were found in 138 patients with EORP. Although most of the identified LCA5 mutations led to a truncated protein, a likely pathogenic missense variant was identified for the first time as a cause of LCA, segregating in 2 families. We also have characterized a novel splicing site mutation at the RNA level, demonstrating that the mutant LCA5 transcript was absent in a patient. All patients carrying LCA5 mutations presented nystagmus, night blindness, and progressive loss of visual acuity and visual field leading to blindness toward the third decade of life. Fundoscopy showed fundus features of pigmentary retinopathy with atrophic macular lesions.

Conclusions: This work reveals a higher frequency of LCA5 mutations in a Spanish LCA cohort than in other populations. This study established gene-specific frequencies and the underlying phenotype of LCA5 mutations in the Spanish population.
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http://dx.doi.org/10.1016/j.ophtha.2013.08.028DOI Listing
January 2014

Pharmacogenomics of anti-platelet therapy focused on peripheral blood cells of coronary arterial disease patients.

Clin Chim Acta 2013 Oct 4;425:9-17. Epub 2013 Jul 4.

School of Pharmaceutical Sciences, University of Sao Paulo, Brazil. Electronic address:

Background: To investigate genes differentially expressed in peripheral blood cells (PBCs) from patients with coronary arterial disease (CAD) under double anti-platelet therapy.

Methods: Twenty-six CAD patients that were submitted to percutaneous coronary intervention (PCI) were selected to participate in this study. These patients took 100mg/day of acetylsalicylic acid (ASA) and 75mg/day of clopidogrel. Blood samples were collected before PCI to evaluate platelet reactivity using VerifyNow ASA and P2Y12 assays (Accumetrics). The patients were stratified into 4 quartiles based on ASA reaction units (ARUs) and P2Y12 reaction units (PRUs). Quartile 1 (Q1) patients were classified as responders and quartile 4 (Q4) patients as non-responders. Global mRNA expression from Q1 to Q4 was analyzed by microarray using the GeneChip Exon 1.0 ST array (Affymetrix) and was confirmed by RT-qPCR.

Results: Patients with ARU or PRU values within the first quartile (Q1, ARU<390 and PRU<151) were considered responders, while those who had ARU or PRU within the fourth quartile (Q4, ARU>467 and PRU>260) were considered nonresponders. The risk factors associated for CAD showed expected frequencies and no difference was found between Q1 and Q4. Microarray analysis identified 117 genes differentially expressed for ASA and 29 for clopidogrel between Q1 and Q4 groups (p<0.01, FC>1.2).

Conclusion: The variation in response to ASA may be related with an increased expression of IGF1 and IGF1R, as well as a response to clopidogrel can be affected by pharmacokinetic change related to the reverse transport pathway by increased expression of ABCC3.
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http://dx.doi.org/10.1016/j.cca.2013.06.021DOI Listing
October 2013

Novel genes detected by transcriptional profiling from whole-blood cells in patients with early onset of acute coronary syndrome.

Clin Chim Acta 2013 Jun 25;421:184-90. Epub 2013 Mar 25.

Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.

Background: Genome-wide expression analysis using microarrays has been used as a research strategy to discovery new biomarkers and candidate genes for a number of diseases. We aim to find new biomarkers for the prediction of acute coronary syndrome (ACS) with a differentially expressed mRNA profiling approach using whole genomic expression analysis in a peripheral blood cell model from patients with early ACS.

Methods And Results: This study was carried out in two phases. On phase 1 a restricted clinical criteria (ACS-Ph1, n=9 and CG-Ph1, n=6) was used in order to select potential mRNA biomarkers candidates. A subsequent phase 2 study was performed using selected phase 1 markers analyzed by RT-qPCR using a larger and independent casuistic (ACS-Ph2, n=74 and CG-Ph2, n=41). A total of 549 genes were found to be differentially expressed in the first 48 h after the ACS-Ph1. Technical and biological validation further confirmed that ALOX15, AREG, BCL2A1, BCL2L1, CA1, COX7B, ECHDC3, IL18R1, IRS2, KCNE1, MMP9, MYL4 and TREML4, are differentially expressed in both phases of this study.

Conclusions: Transcriptomic analysis by microarray technology demonstrated differential expression during a 48 h time course suggesting a potential use of some of these genes as biomarkers for very early stages of ACS, as well as for monitoring early cardiac ischemic recovery.
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http://dx.doi.org/10.1016/j.cca.2013.03.011DOI Listing
June 2013

A genetic case-control study confirms the implication of SMAD7 and TNF locus in the development of proliferative vitreoretinopathy.

Invest Ophthalmol Vis Sci 2013 Mar 5;54(3):1665-78. Epub 2013 Mar 5.

Institute of Applied Ophthalmolbiology (IOBA-Eye Institute), University of Valladolid, Spain.

Purpose: Proliferative vitreoretinopathy (PVR) is still the major cause of failure of retinal detachment (RD) surgery and although the risk for developing this complication is associated with some clinical characteristics, the correlation is far from absolute, raising the possibility of genetic susceptibility. The objective of this study was to analyze the genetic contribution to PVR in patients undergoing RD surgery, the Retina 4 Project.

Methods: A candidate gene association study was conducted in 2006 in a Spanish population of 450 patients suffering from primary rhegmatogenous RD. Replication was carried out in a larger population undergoing RD surgery at several European centers among 546 new patients. Single nucleotide polymorphism (SNP) of 30 genes known to be involved with inflammation were analyzed. For replication stage, those genes previously detected as significantly associated with PVR were genotyped. Distribution of allelic and haplotypic frequencies in case and control group were analyzed. Single and haplotypic analysis were assessed. The Rosenberg two-stage method was used to correct for single and multiple analyses.

Results: After correction for multiple comparisons, four genes were significantly associated with PVR: SMAD7 (P = 0.004), PIK3CG (P = 0.009), TNF locus (P = 0.0005), and TNFR2 (P = 0.019) In the European sample, replication was observed in SMAD7 (P = 0.047) and the TNF locus (P = 0.044).

Conclusions: These results confirm the genetic contribution to PVR and the implication of SMAD7 and TNF locus in the development of PVR. This finding may have implications for understanding the mechanisms of PVR and could provide a potential new therapeutic target for PVR prophylaxis.
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http://dx.doi.org/10.1167/iovs.12-10931DOI Listing
March 2013