- Email: [email protected]
Standing on the Shoulders of Giants: J.A.P. Paré and the Birth of Cardiovascular Genetics
Canadian Journal of Cardiology
-
(2015) 1e4
Viewpoint
and the Standing on the Shoulders of Giants: J.A.P. Pare Birth of Cardiovascular Genetics Srijita Sen-Chowdhry, MBBS, MD (Cantab), FESC,a,b and William J. McKenna, MD, DSc, FRCPa,c a b
Institute of Cardiovascular Science, University College London, London, United Kingdom
Department of Epidemiology, Imperial College, St Mary’s Campus, Norfolk Place, London, United Kingdom c
Heart Hospital, Hamad Medical Corporation, Doha, Qatar
ABSTRACT
RESUM E
Sudden death and stroke afflicted a family from rural Quebec with such frequency as to be called the Coaticook curse by the local community. In Montreal in the late 1950s, a team of physicians led by investigated this family for inherited cardiovascular disJ.A.P. Pare ease. Their efforts resulted in an extensive and now classic description of familial hypertrophic cardiomyopathy. A quarter of a century later, the same family was the subject of linkage analysis and direct sequencing, culminating in the isolation of a mutation in the gene encoding the b myosin heavy chain. MYH7 was the first gene implicated in a cardiovascular disease, which paved the way for identification of mutations in other heritable disorders, mechanistic studies, and clinical applications, such as predictive testing. The present era of cardiovascular genomics arguably had its inception in the clinical ob and his colleagues more than 50 years ago. servations of Dr Pare
rurale du Que bec, une famille avait e te Dans une petite communaute prouve e par les morts subites et les AVC que ses contellement e ce phe nomène la male diction de citoyens avaient surnomme al, à la fin des anne es 1950, une e quipe de Coaticook. À Montre decins mene e par le Dr J.A.P. Pare a e tudie cette famille qui me re ditaire. Ces semblait atteinte d’une maladie cardiovasculaire he lieu à une description de taille e et de sormais clastravaux ont donne sique de la cardiomyopathie hypertrophique familiale. Un quart de siècle plus tard, cette même famille a fait l’objet d’une analyse par ne tique et de se quençage direct qui s’est solde e par la liaison ge couverte d’une mutation du gène codant pour la chaîne lourde de de te le premier gène associe à la la bêta-myosine. Le gène MYH7 a e couverte a ouvert la voie à l’identifimaladie cardiovasculaire. Sa de e à d’autres affections he re ditaires, à des cation de mutations lie tudes me canistiques et à des applications cliniques comme les tests e pistage ge ne tique. On peut donc affirmer que les travaux de de s par le Dr Pare et ses collègues, il y a de cela plus de 50 ans, effectue le premier jalon de la ge nomique cardiovasculaire telle ont constitue que nous la connaissons aujourd’hui.
In the past we spoke of genetics; the term now in vogue is genomics. Renaming of the field reflects the gradual shift in focus from single-gene quests to investigation of the whole genome, but is only the tip of the iceberg.1 The growing interest in gene-gene interactions has rendered the conventional vocabulary of disease-causing mutations and “benign” polymorphisms anachronistic. Replacing it is the more generic terminology of effect sizes and sequence variants, customarily subdivided into rare and common according to mean allele frequency. The study of genetic variation as such necessitates evaluation of not only families but also vast
cohorts. Even the long-accepted dichotomy between simple Mendelian and complex traits has been supplanted by a continuum. At one end is an identifiable primary (causal) gene that interacts with modifiers; the sharing of influence between multiple genes then becomes progressively more important, until the primacy of any individual gene is no longer discernible.2 If turf boundaries seem increasingly blurred, it is because the evolving field calls for a cross-disciplinary approach. The ability to perform statistical analysis of large quantities of data, at one time the province of population geneticists, is now also required of molecular geneticists.1 Interpretation of the data generated entails bioinformatics, which attracts physical and life scientists. The advances in technology that have spurred these developments have also facilitated commercialization of genetic testing, bringing genomics out of the academic laboratory and into the public eye.1,3
Received for publication April 10, 2015. Accepted May 31, 2015. Corresponding author: Dr William J. McKenna, Heart Hospital, Hamad Medical Corporation, PO Box 3050, Doha, Qatar. Tel.: þ974-4439-5300. E-mail: [email protected] See page 3 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2015.05.026 0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
2
Canadian Journal of Cardiology Volume - 2015
and colleagues and published in 1961.5 (B) A photograph of Dr Pare . (C) Figure 1. (A) Shows the original genealogical chart compiled by Dr Pare The revised pedigree constructed for the linkage study in the late 1980s.6 Squares denote men and circles women. The symbols are shaded for those affected, clear for those unaffected, and hatched for those not examined. Slashes indicate deceased family members. (A) Reproduced from et al.5 with permission from Elsevier. (B) Reproduced from Pare 7 with permission from Peter Pare . (C) Reproduced from Jarcho et al.6 with Pare permission from the Massachusetts Medical Society.
Nevertheless, as Allan C. Spralding pointed out, the advent of genomics is not a unique watershed in genetic history. Recognizable in retrospect are 4 successive “revolutionary” eras: classical genetics, molecular genetics, molecular cloning and, most recently, genomics.4 Galvanized by technological advances, each of these eras provided fresh insights into genomes, demanded expansion of the skill set of those working in the field, and enhanced clinical relevance and public interest in their work. Despite the justifiable enthusiasm that hailed each era, however, none proved to be a magic bullet, and each owed much to its predecessors.4 Herein we revisit the roots of cardiovascular genetics, which arguably began with the description of hereditary cardiovascular dysplasiadnow known as hypertrophic cardiomyopathydin a large Canadian family.5 In the fall of 1957, 2 brothers aged 39 and 41 years were coincidentally admitted to the Royal Victoria Hospital in Montreal with unexplained cardiomegaly and a history of cerebrovascular accidents. The family history included a
conspicuously high incidence of strokes and premature sudden deaths (at ages younger than 45 years), to which the local community referred as the Coaticook curse, after the small town in rural Quebec where the family resided. Suspecting an inherited condition, the team of physiciansdled by a chest physician, Dr J.A.P. (Peter) Paredundertook an extensive family study (Fig. 1). Over the following 2 years, they obtained relevant available details on the deceased and evaluated surviving relatives. Initial screening included clinical history, physical examination, electrocardiography, and chest radiography; most of those with abnormalities returned for reassessment 1 year later.5 Because no postmortem examinations had been conducted, relatives served as the primary source of information on the deceased individuals. Presumptive retrospective diagnoses were made if family members recalled symptoms of cardiac disease and/or premature sudden death in the deceased, and corroborated in 2 cases based on archived electrocardiograms.
Sen-Chowdhry and McKenna and the Birth of Cardiovascular Genetics Pare
A 95-year-old relative with a remarkable memory provided much of the early history of his family, including the sudden deaths of his uncle in 1860 and subsequently his cousin. Overall, there was evidence of cardiac disease in 20 living and 10 deceased family members, bringing the total number of affected individuals to 30. An extensive pedigree was compiled (Fig. 1) and the pattern of inheritance was noted to be nonsexlinked (autosomal) dominant.5 Although the phenotypic manifestations of hypertrophic cardiomyopathy are diverse, many of its characteristic features were present in this single kindred. Recurrent symptoms were shortness of breath, chest pain, presyncope, and syncope; the latter was often precipitated by exertion, which suggested left ventricular outflow tract obstruction or inappropriate vasodilation as likely mechanisms. The most frequent electrocardiographic abnormality was flattening or inversion of the T waves in leads V4-V6 and lead aVF. Because ambulatory electrocardiogram (ECG) monitoring was not available in the clinical setting in the late 1950s, there is scant information on the prevalence of supraventricular and ventricular arrhythmia in the family. The resting 12-lead ECG showed sinus rhythm in most cases, the exception being an 18-year-old girl who was found to be in persistent atrial fibrillation. The prominence of cerebrovascular accidents in the family nonetheless suggested that paroxysmal atrial fibrillation may have been relatively common among affected individuals. In the 4 years between commencement of the study and publication of the findings, 5 of the study participants sadly died; autopsies were performed in 3, revealing hypertrophy with a predilection for the left ventricle, myocyte disarray (“muscle fibres... in a peculiar haphazard architectural pattern”), and patchy areas of fibrosis.5 More than a quarter of a century after Dr Pare and his colleagues first studied the kindred, the search was on for the genetic basis of hypertrophic cardiomyopathy. To be suitable for linkage analysis, families with inherited disease ought ideally to fulfil a number of conditions. First, sizeable kindredsdas opposed to small, nuclear familiesdare favoured. Second, although the unknown causal mutation should show relatively high penetrance, the disease that affects the family should be of sufficiently low lethality to permit timely, antemortem diagnosis. An easily recognizable phenotype is also conducive; too much variation in disease expression might complicate identification of the family members who harbour the genetic defect. The key requisite is a large number of living, affected individuals, who can be readily distinguished from their genetically unaffected relatives. In every respect the family described by Dr Pare seemed to fit the bill, so a team led by Christine Seidman arranged a reunion. In her retrospective personal account of the identification of sarcomeric gene mutations in hypertrophic cardiomyopathy, Christine Seidman reflected on how Dr Pare’s rapport with the family had imbued them with so much trust that more than 100 members agreed to participate, despite their limited understanding of the research (Fig. 1).8 Physical examinations, 12-lead ECGs, and echocardiograms were performed at weekend clinics, together with blood sampling for genetic analysis. Laboratory studies established definitive linkage of the disease gene with a chromosome 14q marker, which yielded 2 likely candidate genesdMYH6 and MYH7drespectively encoding the a and b myosin heavy chains.6,8 Fine-structure mapping and direct sequencing
3
ultimately isolated a missense mutation in exon 13 of MYH7, which converts a highly conserved arginine residue (Arg-403) to a glutamine.8,9 MYH7 had become the first gene to be implicated in a cardiovascular disorder. Today, the annual mortality from hypertrophic cardiomyopathy is estimated at 0.5%-2%, thanks partly to development of an evidence-based risk stratification algorithm, coupled with the availability of implantable cardioverter-defibrillators.10,11 Ambulatory ECG monitoring is an integral component of the work-up, at baseline and during follow-up; clinicians are vigilant not only for nonsustained ventricular tachycardia, a predictor of sudden cardiac death, but also for atrial fibrillation, which prompts anticoagulation treatment to reduce the risk of cerebrovascular events.10 From the genetics standpoint, the advent of whole-exome sequencing promises ultimately to obviate the need for linkage studies. The high throughput techniques now available seem worlds apart from the cumbersome direct sequencing procedures on which laboratory technicians relied in bygone eras. Yet, the genomics era is not the pinnacle of genetics research so much as merely another stepping stone. Allan Spralding predicted that genomics will be superseded by a shift in focus from molecules and single cells to multicellular life.4 If so, the field may ultimately come full circle. Integration of genomics with an understanding of complex biological systems will require not only bioinformatics and sophisticated modelling but also detailed phenotypic correlation. In the arena of cardiovascular genetics, there will be renewed need for the very observational and diagnostic skills that enabled Dr Pare and his colleagues to lay its foundation. Dr Pare died in 2013 at the age of 95. A month after his death, his eldest sondeditor-in-chief of the Canadian Respiratory Journaldused its pages to pay tribute to him as a clinician, academic, teacher, and father.7 Despite having a busy practice, Dr Pare’s commitment to his patients was noteworthy, as were his diagnostic instincts and clinical judgement. He was Professor Emeritus of Medicine at McGill University and coauthored 4 editions of the reference textbook, Diagnosis of Diseases of the Chest, widely regarded as a medical classic and still definitive in its field. His students and trainees recollect his “humorous, gentle, and always encouraging” teaching style.7 Outside of medicine, he is remembered for his role in establishing the regional educational system and philanthropic work with the homeless.12 Incredibly, he also managed to be there for his 7 sons and 2 daughters when they needed him. Not surprisingly, patients, colleagues, students, and family members alike held him in high esteem; at 6 foot 4 inches, he must have towered above most of them physically as well.7 As genomics meets the whole organism and clinical skills must again come to the fore, it behooves us to recall that we are standing on the shoulders of giants. Funding Sources The authors were supported by the British Heart Foundation. Disclosures The authors have no conflicts of interest to disclose.
4
References
Canadian Journal of Cardiology Volume - 2015 8. Seidman CE, Seidman JG. Identifying sarcomere gene mutations in HCM: a personal history. Circ Res 2011;108:743-50.
1. Lewis R. You say genomics, I say genetics.. Nature 2005;437:1202-3. 2. Dipple KM, McCabe ER. Modifier genes convert “simple” Mendelian disorders to complex traits. Mol Genet Metab 2000;71:43-50. 3. Sen-Chowdhry S, Jacoby D, McKenna WJ. The implications of inheritance for clinical management. Circ Cardiovasc Genet 2012;5:467-76. 4. Spradling AC. Learning the common language of genetics. Genetics 2006;174:1-3. 5. Pare JA, Fraser RG, Pirozynski WJ, Shanks JA, Stubington D. Hereditary cardiovascular dysplasia. A form of familial cardiomyopathy. Am J Med 1961;31:37-62. 6. Jarcho JA, McKenna W, Pare JA, et al. Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. N Engl J Med 1989;321:1372-8. 7. Pare P. Jules Arthur Peter Pare. Can Respir J 2013;20:80.
9. Geisterfer-Lowrance AA, Kass S, Tanigawa G, et al. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell 1990;62:999-1006. 10. Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:2733-79. 11. Maron BJ, Rowin EJ, Casey SA, et al. Hypertrophic cardiomyopathy in adulthood associated with low cardiovascular mortality with contemporary management strategies. J Am Coll Cardiol 2015;65:1915-28. 12. Jules Arthur Peter Pare MDCM, BSc, FACP, Professor Emeritus of Medicine, McGill University. Obituary. Montreal Gazette February 27, 2013.
-
(2015) 1e4
Viewpoint
and the Standing on the Shoulders of Giants: J.A.P. Pare Birth of Cardiovascular Genetics Srijita Sen-Chowdhry, MBBS, MD (Cantab), FESC,a,b and William J. McKenna, MD, DSc, FRCPa,c a b
Institute of Cardiovascular Science, University College London, London, United Kingdom
Department of Epidemiology, Imperial College, St Mary’s Campus, Norfolk Place, London, United Kingdom c
Heart Hospital, Hamad Medical Corporation, Doha, Qatar
ABSTRACT
RESUM E
Sudden death and stroke afflicted a family from rural Quebec with such frequency as to be called the Coaticook curse by the local community. In Montreal in the late 1950s, a team of physicians led by investigated this family for inherited cardiovascular disJ.A.P. Pare ease. Their efforts resulted in an extensive and now classic description of familial hypertrophic cardiomyopathy. A quarter of a century later, the same family was the subject of linkage analysis and direct sequencing, culminating in the isolation of a mutation in the gene encoding the b myosin heavy chain. MYH7 was the first gene implicated in a cardiovascular disease, which paved the way for identification of mutations in other heritable disorders, mechanistic studies, and clinical applications, such as predictive testing. The present era of cardiovascular genomics arguably had its inception in the clinical ob and his colleagues more than 50 years ago. servations of Dr Pare
rurale du Que bec, une famille avait e te Dans une petite communaute prouve e par les morts subites et les AVC que ses contellement e ce phe nomène la male diction de citoyens avaient surnomme al, à la fin des anne es 1950, une e quipe de Coaticook. À Montre decins mene e par le Dr J.A.P. Pare a e tudie cette famille qui me re ditaire. Ces semblait atteinte d’une maladie cardiovasculaire he lieu à une description de taille e et de sormais clastravaux ont donne sique de la cardiomyopathie hypertrophique familiale. Un quart de siècle plus tard, cette même famille a fait l’objet d’une analyse par ne tique et de se quençage direct qui s’est solde e par la liaison ge couverte d’une mutation du gène codant pour la chaîne lourde de de te le premier gène associe à la la bêta-myosine. Le gène MYH7 a e couverte a ouvert la voie à l’identifimaladie cardiovasculaire. Sa de e à d’autres affections he re ditaires, à des cation de mutations lie tudes me canistiques et à des applications cliniques comme les tests e pistage ge ne tique. On peut donc affirmer que les travaux de de s par le Dr Pare et ses collègues, il y a de cela plus de 50 ans, effectue le premier jalon de la ge nomique cardiovasculaire telle ont constitue que nous la connaissons aujourd’hui.
In the past we spoke of genetics; the term now in vogue is genomics. Renaming of the field reflects the gradual shift in focus from single-gene quests to investigation of the whole genome, but is only the tip of the iceberg.1 The growing interest in gene-gene interactions has rendered the conventional vocabulary of disease-causing mutations and “benign” polymorphisms anachronistic. Replacing it is the more generic terminology of effect sizes and sequence variants, customarily subdivided into rare and common according to mean allele frequency. The study of genetic variation as such necessitates evaluation of not only families but also vast
cohorts. Even the long-accepted dichotomy between simple Mendelian and complex traits has been supplanted by a continuum. At one end is an identifiable primary (causal) gene that interacts with modifiers; the sharing of influence between multiple genes then becomes progressively more important, until the primacy of any individual gene is no longer discernible.2 If turf boundaries seem increasingly blurred, it is because the evolving field calls for a cross-disciplinary approach. The ability to perform statistical analysis of large quantities of data, at one time the province of population geneticists, is now also required of molecular geneticists.1 Interpretation of the data generated entails bioinformatics, which attracts physical and life scientists. The advances in technology that have spurred these developments have also facilitated commercialization of genetic testing, bringing genomics out of the academic laboratory and into the public eye.1,3
Received for publication April 10, 2015. Accepted May 31, 2015. Corresponding author: Dr William J. McKenna, Heart Hospital, Hamad Medical Corporation, PO Box 3050, Doha, Qatar. Tel.: þ974-4439-5300. E-mail: [email protected] See page 3 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2015.05.026 0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
2
Canadian Journal of Cardiology Volume - 2015
and colleagues and published in 1961.5 (B) A photograph of Dr Pare . (C) Figure 1. (A) Shows the original genealogical chart compiled by Dr Pare The revised pedigree constructed for the linkage study in the late 1980s.6 Squares denote men and circles women. The symbols are shaded for those affected, clear for those unaffected, and hatched for those not examined. Slashes indicate deceased family members. (A) Reproduced from et al.5 with permission from Elsevier. (B) Reproduced from Pare 7 with permission from Peter Pare . (C) Reproduced from Jarcho et al.6 with Pare permission from the Massachusetts Medical Society.
Nevertheless, as Allan C. Spralding pointed out, the advent of genomics is not a unique watershed in genetic history. Recognizable in retrospect are 4 successive “revolutionary” eras: classical genetics, molecular genetics, molecular cloning and, most recently, genomics.4 Galvanized by technological advances, each of these eras provided fresh insights into genomes, demanded expansion of the skill set of those working in the field, and enhanced clinical relevance and public interest in their work. Despite the justifiable enthusiasm that hailed each era, however, none proved to be a magic bullet, and each owed much to its predecessors.4 Herein we revisit the roots of cardiovascular genetics, which arguably began with the description of hereditary cardiovascular dysplasiadnow known as hypertrophic cardiomyopathydin a large Canadian family.5 In the fall of 1957, 2 brothers aged 39 and 41 years were coincidentally admitted to the Royal Victoria Hospital in Montreal with unexplained cardiomegaly and a history of cerebrovascular accidents. The family history included a
conspicuously high incidence of strokes and premature sudden deaths (at ages younger than 45 years), to which the local community referred as the Coaticook curse, after the small town in rural Quebec where the family resided. Suspecting an inherited condition, the team of physiciansdled by a chest physician, Dr J.A.P. (Peter) Paredundertook an extensive family study (Fig. 1). Over the following 2 years, they obtained relevant available details on the deceased and evaluated surviving relatives. Initial screening included clinical history, physical examination, electrocardiography, and chest radiography; most of those with abnormalities returned for reassessment 1 year later.5 Because no postmortem examinations had been conducted, relatives served as the primary source of information on the deceased individuals. Presumptive retrospective diagnoses were made if family members recalled symptoms of cardiac disease and/or premature sudden death in the deceased, and corroborated in 2 cases based on archived electrocardiograms.
Sen-Chowdhry and McKenna and the Birth of Cardiovascular Genetics Pare
A 95-year-old relative with a remarkable memory provided much of the early history of his family, including the sudden deaths of his uncle in 1860 and subsequently his cousin. Overall, there was evidence of cardiac disease in 20 living and 10 deceased family members, bringing the total number of affected individuals to 30. An extensive pedigree was compiled (Fig. 1) and the pattern of inheritance was noted to be nonsexlinked (autosomal) dominant.5 Although the phenotypic manifestations of hypertrophic cardiomyopathy are diverse, many of its characteristic features were present in this single kindred. Recurrent symptoms were shortness of breath, chest pain, presyncope, and syncope; the latter was often precipitated by exertion, which suggested left ventricular outflow tract obstruction or inappropriate vasodilation as likely mechanisms. The most frequent electrocardiographic abnormality was flattening or inversion of the T waves in leads V4-V6 and lead aVF. Because ambulatory electrocardiogram (ECG) monitoring was not available in the clinical setting in the late 1950s, there is scant information on the prevalence of supraventricular and ventricular arrhythmia in the family. The resting 12-lead ECG showed sinus rhythm in most cases, the exception being an 18-year-old girl who was found to be in persistent atrial fibrillation. The prominence of cerebrovascular accidents in the family nonetheless suggested that paroxysmal atrial fibrillation may have been relatively common among affected individuals. In the 4 years between commencement of the study and publication of the findings, 5 of the study participants sadly died; autopsies were performed in 3, revealing hypertrophy with a predilection for the left ventricle, myocyte disarray (“muscle fibres... in a peculiar haphazard architectural pattern”), and patchy areas of fibrosis.5 More than a quarter of a century after Dr Pare and his colleagues first studied the kindred, the search was on for the genetic basis of hypertrophic cardiomyopathy. To be suitable for linkage analysis, families with inherited disease ought ideally to fulfil a number of conditions. First, sizeable kindredsdas opposed to small, nuclear familiesdare favoured. Second, although the unknown causal mutation should show relatively high penetrance, the disease that affects the family should be of sufficiently low lethality to permit timely, antemortem diagnosis. An easily recognizable phenotype is also conducive; too much variation in disease expression might complicate identification of the family members who harbour the genetic defect. The key requisite is a large number of living, affected individuals, who can be readily distinguished from their genetically unaffected relatives. In every respect the family described by Dr Pare seemed to fit the bill, so a team led by Christine Seidman arranged a reunion. In her retrospective personal account of the identification of sarcomeric gene mutations in hypertrophic cardiomyopathy, Christine Seidman reflected on how Dr Pare’s rapport with the family had imbued them with so much trust that more than 100 members agreed to participate, despite their limited understanding of the research (Fig. 1).8 Physical examinations, 12-lead ECGs, and echocardiograms were performed at weekend clinics, together with blood sampling for genetic analysis. Laboratory studies established definitive linkage of the disease gene with a chromosome 14q marker, which yielded 2 likely candidate genesdMYH6 and MYH7drespectively encoding the a and b myosin heavy chains.6,8 Fine-structure mapping and direct sequencing
3
ultimately isolated a missense mutation in exon 13 of MYH7, which converts a highly conserved arginine residue (Arg-403) to a glutamine.8,9 MYH7 had become the first gene to be implicated in a cardiovascular disorder. Today, the annual mortality from hypertrophic cardiomyopathy is estimated at 0.5%-2%, thanks partly to development of an evidence-based risk stratification algorithm, coupled with the availability of implantable cardioverter-defibrillators.10,11 Ambulatory ECG monitoring is an integral component of the work-up, at baseline and during follow-up; clinicians are vigilant not only for nonsustained ventricular tachycardia, a predictor of sudden cardiac death, but also for atrial fibrillation, which prompts anticoagulation treatment to reduce the risk of cerebrovascular events.10 From the genetics standpoint, the advent of whole-exome sequencing promises ultimately to obviate the need for linkage studies. The high throughput techniques now available seem worlds apart from the cumbersome direct sequencing procedures on which laboratory technicians relied in bygone eras. Yet, the genomics era is not the pinnacle of genetics research so much as merely another stepping stone. Allan Spralding predicted that genomics will be superseded by a shift in focus from molecules and single cells to multicellular life.4 If so, the field may ultimately come full circle. Integration of genomics with an understanding of complex biological systems will require not only bioinformatics and sophisticated modelling but also detailed phenotypic correlation. In the arena of cardiovascular genetics, there will be renewed need for the very observational and diagnostic skills that enabled Dr Pare and his colleagues to lay its foundation. Dr Pare died in 2013 at the age of 95. A month after his death, his eldest sondeditor-in-chief of the Canadian Respiratory Journaldused its pages to pay tribute to him as a clinician, academic, teacher, and father.7 Despite having a busy practice, Dr Pare’s commitment to his patients was noteworthy, as were his diagnostic instincts and clinical judgement. He was Professor Emeritus of Medicine at McGill University and coauthored 4 editions of the reference textbook, Diagnosis of Diseases of the Chest, widely regarded as a medical classic and still definitive in its field. His students and trainees recollect his “humorous, gentle, and always encouraging” teaching style.7 Outside of medicine, he is remembered for his role in establishing the regional educational system and philanthropic work with the homeless.12 Incredibly, he also managed to be there for his 7 sons and 2 daughters when they needed him. Not surprisingly, patients, colleagues, students, and family members alike held him in high esteem; at 6 foot 4 inches, he must have towered above most of them physically as well.7 As genomics meets the whole organism and clinical skills must again come to the fore, it behooves us to recall that we are standing on the shoulders of giants. Funding Sources The authors were supported by the British Heart Foundation. Disclosures The authors have no conflicts of interest to disclose.
4
References
Canadian Journal of Cardiology Volume - 2015 8. Seidman CE, Seidman JG. Identifying sarcomere gene mutations in HCM: a personal history. Circ Res 2011;108:743-50.
1. Lewis R. You say genomics, I say genetics.. Nature 2005;437:1202-3. 2. Dipple KM, McCabe ER. Modifier genes convert “simple” Mendelian disorders to complex traits. Mol Genet Metab 2000;71:43-50. 3. Sen-Chowdhry S, Jacoby D, McKenna WJ. The implications of inheritance for clinical management. Circ Cardiovasc Genet 2012;5:467-76. 4. Spradling AC. Learning the common language of genetics. Genetics 2006;174:1-3. 5. Pare JA, Fraser RG, Pirozynski WJ, Shanks JA, Stubington D. Hereditary cardiovascular dysplasia. A form of familial cardiomyopathy. Am J Med 1961;31:37-62. 6. Jarcho JA, McKenna W, Pare JA, et al. Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. N Engl J Med 1989;321:1372-8. 7. Pare P. Jules Arthur Peter Pare. Can Respir J 2013;20:80.
9. Geisterfer-Lowrance AA, Kass S, Tanigawa G, et al. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell 1990;62:999-1006. 10. Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:2733-79. 11. Maron BJ, Rowin EJ, Casey SA, et al. Hypertrophic cardiomyopathy in adulthood associated with low cardiovascular mortality with contemporary management strategies. J Am Coll Cardiol 2015;65:1915-28. 12. Jules Arthur Peter Pare MDCM, BSc, FACP, Professor Emeritus of Medicine, McGill University. Obituary. Montreal Gazette February 27, 2013.