Canadian Journal of Cardiology 31 (2015) 1305e1308

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
Institute of Cardiovascular Science, University College London, London, United Kingdom
b
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 Dans une petite communaute  rurale du Que bec, une famille avait e  te

such frequency as to be called the Coaticook curse by the local com- tellement e prouvee par les morts subites et les AVC que ses con-
munity. In Montreal in the late 1950s, a team of physicians led by citoyens avaient surnomme  ce phe nomène la male diction de
 investigated this family for inherited cardiovascular dis-
J.A.P. Pare Coaticook. À Montre al, à la fin des anne es 1950, une e quipe de
ease. Their efforts resulted in an extensive and now classic description me decins mene e par le Dr J.A.P. Pare  a e tudie cette famille qui
of familial hypertrophic cardiomyopathy. A quarter of a century later, semblait atteinte d’une maladie cardiovasculaire he re
ditaire. Ces
the same family was the subject of linkage analysis and direct travaux ont donne  lieu à une description de taille
e et desormais clas-
sequencing, culminating in the isolation of a mutation in the gene sique de la cardiomyopathie hypertrophique familiale. Un quart de
encoding the b myosin heavy chain. MYH7 was the first gene impli- siècle plus tard, cette même famille a fait l’objet d’une analyse par
cated in a cardiovascular disease, which paved the way for identifi- liaison ge ne
tique et de se quençage direct qui s’est solde e par la
cation of mutations in other heritable disorders, mechanistic studies, decouverte d’une mutation du gène codant pour la chaîne lourde de
and clinical applications, such as predictive testing. The present era of la bêta-myosine. Le gène MYH7 a e  te
 le premier gène associe  à la
cardiovascular genomics arguably had its inception in the clinical ob- maladie cardiovasculaire. Sa de couverte a ouvert la voie à l’identifi-
servations of Dr Pare  and his colleagues more than 50 years ago. cation de mutations lie e à d’autres affections he re
ditaires, à des
tudes me
e canistiques et à des applications cliniques comme les tests
de de pistage ge netique. On peut donc affirmer que les travaux
s par le Dr Pare
effectue  et ses collègues, il y a de cela plus de 50 ans,
ont constitue le premier jalon de la ge nomique cardiovasculaire telle
que nous la connaissons aujourd’hui.

In the past we spoke of genetics; the term now in vogue is cohorts. Even the long-accepted dichotomy between simple
genomics. Renaming of the field reflects the gradual shift in Mendelian and complex traits has been supplanted by a
focus from single-gene quests to investigation of the whole continuum. At one end is an identifiable primary (causal)
genome, but is only the tip of the iceberg.1 The growing gene that interacts with modifiers; the sharing of influence
interest in gene-gene interactions has rendered the conven- between multiple genes then becomes progressively more
tional vocabulary of disease-causing mutations and “benign” important, until the primacy of any individual gene is no
polymorphisms anachronistic. Replacing it is the more longer discernible.2
generic terminology of effect sizes and sequence variants, If turf boundaries seem increasingly blurred, it is because
customarily subdivided into rare and common according to the evolving field calls for a cross-disciplinary approach. The
mean allele frequency. The study of genetic variation as such ability to perform statistical analysis of large quantities of data,
necessitates evaluation of not only families but also vast at one time the province of population geneticists, is now also
required of molecular geneticists.1 Interpretation of the data
Received for publication April 10, 2015. Accepted May 31, 2015.
generated entails bioinformatics, which attracts physical and
life scientists. The advances in technology that have spurred
Corresponding author: Dr William J. McKenna, Heart Hospital, Hamad
Medical Corporation, PO Box 3050, Doha, Qatar. Tel.: þ974-4439-5300.
these developments have also facilitated commercialization of
E-mail: [email protected] genetic testing, bringing genomics out of the academic labo-
See page 1307 for disclosure information. ratory and into the public eye.1,3

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.
1306 Canadian Journal of Cardiology
Volume 31 2015

Figure 1. (A) Shows the original genealogical chart compiled by Dr Pare and colleagues and published in 1961.5 (B) A photograph of Dr Pare
. (C)
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
Pare 7 with permission from Peter Pare
. (C) Reproduced from Jarcho et al.6 with
permission from the Massachusetts Medical Society.

Nevertheless, as Allan C. Spralding pointed out, the advent conspicuously high incidence of strokes and premature sud-
of genomics is not a unique watershed in genetic history. den deaths (at ages younger than 45 years), to which the local
Recognizable in retrospect are 4 successive “revolutionary” eras: community referred as the Coaticook curse, after the small
classical genetics, molecular genetics, molecular cloning and, town in rural Quebec where the family resided. Suspecting an
most recently, genomics.4 Galvanized by technological ad- inherited condition, the team of physiciansdled by a chest
vances, each of these eras provided fresh insights into genomes, physician, Dr J.A.P. (Peter) Paredundertook an extensive
demanded expansion of the skill set of those working in the family study (Fig. 1). Over the following 2 years, they ob-
field, and enhanced clinical relevance and public interest in tained relevant available details on the deceased and evaluated
their work. Despite the justifiable enthusiasm that hailed each surviving relatives. Initial screening included clinical history,
era, however, none proved to be a magic bullet, and each owed physical examination, electrocardiography, and chest radiog-
much to its predecessors.4 Herein we revisit the roots of car- raphy; most of those with abnormalities returned for reas-
diovascular genetics, which arguably began with the description sessment 1 year later.5
of hereditary cardiovascular dysplasiadnow known as hyper- Because no postmortem examinations had been conduct-
trophic cardiomyopathydin a large Canadian family.5 ed, relatives served as the primary source of information on
In the fall of 1957, 2 brothers aged 39 and 41 years were the deceased individuals. Presumptive retrospective diagnoses
coincidentally admitted to the Royal Victoria Hospital in were made if family members recalled symptoms of cardiac
Montreal with unexplained cardiomegaly and a history of disease and/or premature sudden death in the deceased, and
cerebrovascular accidents. The family history included a corroborated in 2 cases based on archived electrocardiograms.
Sen-Chowdhry and McKenna 1307
 and the Birth of Cardiovascular Genetics
Pare

A 95-year-old relative with a remarkable memory provided ultimately isolated a missense mutation in exon 13 of MYH7,
much of the early history of his family, including the sudden which converts a highly conserved arginine residue (Arg-403)
deaths of his uncle in 1860 and subsequently his cousin. to a glutamine.8,9 MYH7 had become the first gene to be
Overall, there was evidence of cardiac disease in 20 living and implicated in a cardiovascular disorder.
10 deceased family members, bringing the total number of Today, the annual mortality from hypertrophic cardio-
affected individuals to 30. An extensive pedigree was compiled myopathy is estimated at 0.5%-2%, thanks partly to devel-
(Fig. 1) and the pattern of inheritance was noted to be nonsex- opment of an evidence-based risk stratification algorithm,
linked (autosomal) dominant.5 coupled with the availability of implantable cardioverter-de-
Although the phenotypic manifestations of hypertrophic fibrillators.10,11 Ambulatory ECG monitoring is an integral
cardiomyopathy are diverse, many of its characteristic features component of the work-up, at baseline and during follow-up;
were present in this single kindred. Recurrent symptoms were clinicians are vigilant not only for nonsustained ventricular
shortness of breath, chest pain, presyncope, and syncope; the tachycardia, a predictor of sudden cardiac death, but also for
latter was often precipitated by exertion, which suggested left atrial fibrillation, which prompts anticoagulation treatment to
ventricular outflow tract obstruction or inappropriate vasodi- reduce the risk of cerebrovascular events.10 From the genetics
lation as likely mechanisms. The most frequent electrocardio- standpoint, the advent of whole-exome sequencing promises
graphic abnormality was flattening or inversion of the T waves ultimately to obviate the need for linkage studies. The high
in leads V4-V6 and lead aVF. Because ambulatory electrocar- throughput techniques now available seem worlds apart from
diogram (ECG) monitoring was not available in the clinical the cumbersome direct sequencing procedures on which lab-
setting in the late 1950s, there is scant information on the oratory technicians relied in bygone eras. Yet, the genomics
prevalence of supraventricular and ventricular arrhythmia in era is not the pinnacle of genetics research so much as merely
the family. The resting 12-lead ECG showed sinus rhythm in another stepping stone. Allan Spralding predicted that geno-
most cases, the exception being an 18-year-old girl who was mics will be superseded by a shift in focus from molecules and
found to be in persistent atrial fibrillation. The prominence of single cells to multicellular life.4 If so, the field may ultimately
cerebrovascular accidents in the family nonetheless suggested come full circle. Integration of genomics with an under-
that paroxysmal atrial fibrillation may have been relatively standing of complex biological systems will require not only
common among affected individuals. In the 4 years between bioinformatics and sophisticated modelling but also detailed
commencement of the study and publication of the findings, 5 phenotypic correlation. In the arena of cardiovascular genetics,
of the study participants sadly died; autopsies were performed there will be renewed need for the very observational and
in 3, revealing hypertrophy with a predilection for the left diagnostic skills that enabled Dr Pare and his colleagues to lay
ventricle, myocyte disarray (“muscle fibres... in a peculiar its foundation.
haphazard architectural pattern”), and patchy areas of fibrosis.5 Dr Pare died in 2013 at the age of 95. A month after his
More than a quarter of a century after Dr Pare and his death, his eldest sondeditor-in-chief of the Canadian Res-
colleagues first studied the kindred, the search was on for the piratory Journaldused its pages to pay tribute to him as a
genetic basis of hypertrophic cardiomyopathy. To be suitable clinician, academic, teacher, and father.7 Despite having a
for linkage analysis, families with inherited disease ought busy practice, Dr Pare’s commitment to his patients was
ideally to fulfil a number of conditions. First, sizeable noteworthy, as were his diagnostic instincts and clinical
kindredsdas opposed to small, nuclear familiesdare fav- judgement. He was Professor Emeritus of Medicine at
oured. Second, although the unknown causal mutation should McGill University and coauthored 4 editions of the reference
show relatively high penetrance, the disease that affects the textbook, Diagnosis of Diseases of the Chest, widely regarded as
family should be of sufficiently low lethality to permit timely, a medical classic and still definitive in its field. His students
antemortem diagnosis. An easily recognizable phenotype is and trainees recollect his “humorous, gentle, and always
also conducive; too much variation in disease expression encouraging” teaching style.7 Outside of medicine, he is
might complicate identification of the family members who remembered for his role in establishing the regional educa-
harbour the genetic defect. The key requisite is a large number tional system and philanthropic work with the homeless.12
of living, affected individuals, who can be readily distin- Incredibly, he also managed to be there for his 7 sons and
guished from their genetically unaffected relatives. 2 daughters when they needed him. Not surprisingly, pa-
In every respect the family described by Dr Pare seemed to tients, colleagues, students, and family members alike held
fit the bill, so a team led by Christine Seidman arranged a him in high esteem; at 6 foot 4 inches, he must have towered
reunion. In her retrospective personal account of the identi- above most of them physically as well.7 As genomics meets
fication of sarcomeric gene mutations in hypertrophic car- the whole organism and clinical skills must again come to the
diomyopathy, Christine Seidman reflected on how Dr Pare’s fore, it behooves us to recall that we are standing on the
rapport with the family had imbued them with so much trust shoulders of giants.
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 Funding Sources
performed at weekend clinics, together with blood sampling The authors were supported by the British Heart
for genetic analysis. Laboratory studies established definitive Foundation.
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 Disclosures
chains.6,8 Fine-structure mapping and direct sequencing The authors have no conflicts of interest to disclose.
1308 Canadian Journal of Cardiology
Volume 31 2015

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