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
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 conven-
tional 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
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: w.mckenna@ucl.ac.uk
See page 1307 for disclosure information.
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 labo-
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
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 ad-
vances, 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 car-
diovascular genetics, which arguably began with the description
of hereditary cardiovascular dysplasiadnow known as hyper-
trophic 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 sud-
den 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 ob-
tained relevant available details on the deceased and evaluated
surviving relatives. Initial screening included clinical history,
physical examination, electrocardiography, and chest radiog-
raphy; most of those with abnormalities returned for reas-
sessment 1 year later.5
Because no postmortem examinations had been conduct-
ed, 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 nonsex-
linked (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 vasodi-
lation as likely mechanisms. The most frequent electrocardio-
graphic abnormality was flattening or inversion of the T waves
in leads V4-V6 and lead aVF. Because ambulatory electrocar-
diogram (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 fav-
oured. 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 distin-
guished 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 identi-
fication of sarcomeric gene mutations in hypertrophic car-
diomyopathy, 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
1307
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 cardio-
myopathy is estimated at 0.5%-2%, thanks partly to devel-
opment of an evidence-based risk stratification algorithm,
coupled with the availability of implantable cardioverter-de-
fibrillators.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 lab-
oratory 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 geno-
mics 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 under-
standing 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 Res-
piratory 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 educa-
tional 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, pa-
tients, 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.
1308
References
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 inheri-
tance 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.
Canadian Journal of Cardiology
Volume 31 2015
8. Seidman CE, Seidman JG. Identifying sarcomere gene mutations in
HCM: a personal history. Circ Res 2011;108:743-50.
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 Cardiomy-
opathy 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 contempo-
rary 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.