Breed Predispositions to Disease in Dogs and Cats E-Book

Alex Gough

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch
• Veröffentlichungsjahr: 2018

Seitenzahl: 1068

Beschreibung

Breed Predispositions to Disease in Dogs and Cats, Third Edition provides a comprehensive exploration of current knowledge of breed predispositions based on rigorous examination of primary research. * Incorporates the latest research, new testing methods, and newly-discovered predispositions and diseases * Provides expanded information on genetics, epidemiology, and longevity * Includes key characteristics of diseases, including pathogenesis, genetics, risks, and common presentations * Indexes dogs and cats by breed, with listings of common inherited and predisposed disorders organized by body system * Includes absolute and relative frequency/occurrence data for conditions, along with references to further information

Leseprobe

Breed Predispositions to Disease in Dogs and Cats

THIRD EDITION

Alex Gough

Bath Veterinary Referrals, Bath, UK

Alison Thomas

Blue Cross Animal Hospital Victoria, London, UK

Dan O’Neill

Royal Veterinary College, London, UK

This edition first published 2018© 2018 John Wiley & Sons Ltd

Edition HistoryJohn Wiley & Sons (1e, 2004)John Wiley & Sons (2e, 2010)

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Library of Congress Cataloging‐in‐Publication Data

Names: Gough, Alex, author. | Thomas, Alison, 1964– author. | O’Neill, Dan (Dan G.), author.Title: Breed predispositions to disease in dogs and cats / Alex Gough, Alison Thomas, Dan O’Neill.Description: Third edition. | Hoboken, NJ : Wiley, [2018] | Includes bibliographical references. |Identifiers: LCCN 2017043483 (print) | LCCN 2017055418 (ebook) | ISBN 9781119225553 (pdf) | ISBN 9781119225577 (epub) | ISBN 9781119225546 (pbk.)Subjects: LCSH: Dogs–Diseases. | Cats–Diseases. | MESH: Dog Diseases–genetics | Cat Diseases–genetics | Genetic Predisposition to Disease | PedigreeClassification: LCC SF991 (ebook) | LCC SF991 .G67 2018 (print) | NLM SF 991 | DDC 636.7/089607–dc23LC record available at https://lccn.loc.gov/2017043483

Cover Design: WileyCover Image: (Center right) Labrador retriever © Alison Thomas; (Top left) Cat: Seal point Ragdoll, (Bottom left) Dog: French Bulldog © Dan O’Neill

Alex Gough

To loved ones, friends and colleagues, and of course to my wife Naomi and daughter Abigail for bearing with me through another huge project.

Alison Thomas

To all the wonderful colleagues I have had the pleasure of working with over the years. Most of all to my partner Richard, and children Tom and Harry, for making my life so much fun.

Dan O’Neill

To my wife, best friend and inspiration, Joanne. And to my three children and lights of my life, Alistair, Megan and Clodagh. Thank you each for being you.

This book is also dedicated to all those vets suffering from mental illness, and particularly to those who have lost their lives due to this common condition affecting our profession.

Author Biographies

Alex Gough MA VetMB CertSAM CertVC PGCert MRCVS

Head of Medicine Referrals, Bath Veterinary Referrals

Alex graduated from Cambridge University Vet School in 1996 and achieved RCVS certificates in Small Animal Medicine and Veterinary Cardiology, as well as a human Postgraduate Certificate in Neuroimaging for Research from Edinburgh University. He worked in mixed, mainly small animal practice for six years, then in referral practice, seeing referrals in medicine, cardiology and neurology, with a particular interest in medical neurology. He is the author of Differential Diagnosis in Small Animal Medicine (2007), has written a column summarizing the latest research for the Veterinary Times since 2003 as well as chapters on neurology and clinical genetics in two BSAVA manuals, and sits on the advisory clinical board of a large veterinary group. In his spare time, he writes historical fiction novels and plays guitar.

Alison Thomas BVSc, Cert SAM, MRCVS

Senior Veterinary Surgeon, Victoria Hospital, Blue Cross

Clinical Leadership Team, Blue Cross

Alison graduated from Liverpool University in 1987 and has spent most of her career working in charity small animal practice. After two years in private practice in Aylesbury, she moved to Asia, spending two years in private practice in Singapore, followed by seven years at the SPCA in Hong Kong. Since 1998 she has worked at Blue Cross in Victoria, London, becoming Senior Veterinary Surgeon in 2007 and joining the newly formed Clinical Leadership Team of Blue Cross in 2016. She gained the RCVS Certificate in Small Animal Medicine in 2001, and was awarded Advanced Practitioner Status in Small Animal Medicine in 2017. In her spare time she enjoys hiking, travelling and reading.

Dan O’Neill MVB BSc(hons) GPCert(SAP) GPCert(FelP) GPCert(Derm) GPCert(B&PS) MSc(VetEpi) PhD MRCVS

Senior Lecturer, Companion Animal Epidemiology, Royal Veterinary College

After graduating from Dublin Vet School in 1987, Dan worked in industry and general practice for 22 years, latterly running his own companion animal practice in Petts Wood, Kent, for 12 years. During these years, he was awarded additional qualifications in pharmacology, general practice, dermatology, feline practice and business management. In 2009 he undertook an MSc supported by BBSRC and then a PhD supported by the RSPCA in veterinary epidemiology at the RVC to develop the VetCompass programme of primary‐care veterinary clinical research. After postdoctoral posts supported by Dogs Trust and Kennel Club Charitable Trust, Dan was appointed as Senior Lecturer in Companion Animal Epidemiology at the RVC in 2017. As well as teaching and publishing, Dan focuses on expanding VetCompass internationally, with particular emphasis on breed‐related health. In his spare time, he is a keen ITF taekwondo enthusiast and currently holds a 2nd Dan black belt.

Foreword

For anyone interested in the health and welfare of dogs and cats, there are few topics that engender such emotional energy, diverse opinion and heated debate as the potential negative impacts of selective breeding on canine and feline disease occurrence, and the optimal ways to manage and/or eliminate such impacts. But energy, opinion and debate can only bring true positive change when they are based on good evidence. In this respect, the third edition of Breed Predispositions to Disease in Dogs and Cats is hugely timely. The book comes not only at a time of increasing awareness of the impacts that breed characteristics may have on health, but also when there is growing appreciation of the glaring underuse of objective data to support traditional perceptions and opinions which have become accepted as ‘fact’ in breeding folklore and veterinary science. This book aims to remove the roles of speculation, opinion and anecdote from the discussion on breed health issues and instead to refocus and underpin these discussions based on solid evidence‐based principles.

There is no doubt that the Bateson Report on pedigree dog health and its far‐reaching recommendations (Bateson, 2010), the creation of the Royal College of Veterinary Surgeons’ RCVS Knowledge initiative to promote the generation and application of veterinary clinical evidence (RCVS Knowledge, 2017) and a general increase in commitment to evidence based veterinary medicine over the past decade have resulted in a greater appreciation of the need for reliable evidence on the health impacts of breed characteristics in dogs and cats. Fortunately, this awareness of the need for valid evidence has coincided with the development of exciting new tools which allow us to collect and interpret large volumes of relevant data from primary and referral veterinary practices and to analyse these in robust and less biased ways. As a result, for the first time, we are increasingly able to provide some reliable real‐world context to the likely impact of breed characteristics on animal health and welfare. The development and international adoption of standardized systems of nomenclature such as the VeNom initiative (VeNom Coding Group, 2017) and ground‐breaking research tools such as the Royal Veterinary College’s VetCompass Programme (VetCompass, 2017) allow researchers to explore vast amounts of clinical data from first‐opinion and referral veterinary practices. These developments have transformed how we can investigate companion animal diseases and their impact on animals, their owners and their breeders. The era of ‘Big Data’ for companion animals and its impact on animal health and welfare is now truly upon us.

Realization of the powers from developments such as these means that this new edition of Breed Predispositions to Disease in Dogs and Cats really does herald a new and more valid perspective in our understanding of the types of disorders and their likely impact on different dog and cat breeds. The new edition has been completely rewritten using ‘evidence‐based veterinary medicine’ criteria that are applied to international data and consequently provides an accurate reference resource on disease predispositions that is relevant to breeds from all corners of the world. The information is comprehensive and detailed but presented in a readily understandable and searchable format. Prevalence, odds and risk ratio values, as well as study design details, are provided so that the more motivated reader can go beyond an awareness that a predisposition has been reported and start to examine the context and strength of the reported associations. This book truly is a cornucopia of breed health information.

This third edition will become an invaluable and constant resource for students, vets, breeders, owners, scientists and indeed anyone interested in companion animal welfare. We are privileged to live at a pivotal tipping point in the generation and application of evidence for better decision‐making in companion animal health. This book will play a key role in centralizing our current knowledge into a single resource, and is thereby a torch‐bearer that will finally enable us to move beyond endless circular discussion to positive action that will benefit the welfare of our cats and dogs.

Professor David Church BVSc PhD MACVSc FHEA MRCVS

Deputy Principal and Professor of Small Animal Studies, The Royal Veterinary College

Preface

It is widely accepted that almost all dog and cat breeds have specific diseases to which they are particularly prone (i.e. predisposed). Indeed, many textbooks and published research papers include lists of breed predispositions as a standard feature when describing specific disease conditions. To extend this focus, the first edition of Breed Predispositions to Disease in Dogs and Cats, published in 2004, aimed to provide a single reference resource for breed predispositions that would better illuminate our understanding of breed health (Gough & Thomas, 2004). The concept for the first edition was born during discussions between the two original authors (Alex Gough and Alison Thomas) while preparing for their RCVS Certificate in Small Animal Medicine exams in 2001. This book was the first of its kind to focus purely on breed‐specific predispositions and was widely welcomed by academics, veterinarians, breeders and owners. That original edition was compiled mainly from secondary sources of evidence such as textbooks, reviews and conference proceedings and did not provide detailed reference citations for all the breed–disease combinations reported. The second edition, published in 2010, redressed many of these shortcomings and was updated with more recent publications while also ensuring that every cited disease had at least one supporting reference. However, much of the disease information still came from secondary sources such as textbooks, review articles and conference proceedings. The implication of this was that the second edition was substantially reliant on expert opinion. At that time, almost a decade ago, this approach may have been acceptable, but as we progress into the modern age of evidence‐based veterinary medicine (EBVM), expert opinion is now generally considered to be weak evidence, and reliance should instead be placed on the results of original research (Holmes & Ramey, 2007).

In consequence, preparations began for a third edition that would have a strong emphasis on improved academic rigour, better compliance with the modern principles of EBVM and a sound epidemiological infrastructure. To meet these lofty aspirations, Alex and Alison enlisted Dr Dan O’Neill to join as a third co‐author, to ensure high epidemiological standards and also to reduce the individual workload for each author. Dan is an epidemiologist working on the VetCompass Programme at the Royal Veterinary College (VetCompass, 2017), but with that rare academic attribute of essentially still being a general veterinary practitioner. We are confident that this third edition has achieved our academic goals – but we must also sadly report that we failed in our aspiration to reduce the workload. Indeed, it was quite the reverse, as the new perspectives introduced by Dan entailed a complete rewrite. Ah well, you can’t win them all – but we do hope that you enjoy the end result of our combined labours.

For this new edition, we have consulted and referenced primary sources of evidence almost exclusively (i.e. the original published papers that reported the primary research) and have restricted inclusion to just those diseases where primary research identified sufficient evidence for the existence of a breed predisposition. As might be expected, this new approach led to some challenges and several discussions between the authors on the optimal threshold of evidence for disease inclusion. During our rewrite, we became painfully aware of just how little evidence actually exists for much of what we may ‘believe’ to be true about companion animal health. When we examined the literature closely, many of the predispositions commonly reported as ‘knowns’ in textbooks and introductions to peer‐reviewed publications had very little, if any, reliable supporting evidence. This realization reinforced our determination that the new edition should follow rigorous evidence‐based principles, but it also meant that the new book would entail a total rewrite, with substantial work required to freshly identify those diseases with and without a solid evidence base. We found ourselves painfully deleting many conditions that had been included in the previous book based on expert opinion but which lacked adequate evidence. ‘Believing in a predisposition’ and ‘having evidence for a predisposition’ are not always the same thing. The positive side of our new EBVM approach, however, was a refreshing discovery that our new detailed trawl of the primary literature led us to identify many new breed–disease combinations that had not made it into the previous two editions. This may have been because the predisposition was first reported after the second edition was published or because our previous reliance on expert opinion had failed to uncover the association.

Our new search methods and inclusion criteria are described more fully in the Methods section. We hope that these changes support a more robust and defensible evidential and scientific body of information in this third edition, which also includes additional supporting information for breed predispositions where possible. Such additional information may describe the population studied in the original papers – such as geographical location, referral or general practice population (many academic papers are based on referral populations, and their results do not necessarily generalize well to the populations of patients commonly seen in general practice) – while the date of the referenced papers may assist with a perspective on the temporal relevance of the results. Information is also provided on the comparator populations used in the studies (e.g. crossbreds or all study dogs) and the numerical results, which show the strength of the reported predisposition (e.g. odds ratio or prevalence). Taken together, these new segments of information should help the reader to piece together the likelihood of the reported predispositions being real and relevant in relation to his or her own personal animals and interests. In the first and second editions, the research was divided between the authors by body system. For this third edition, we have instead divided the research alphabetically by breed. Consequently, some differences in writing style and emphasis may be apparent between the authors’ sections. However, by sticking to pre‐agreed methods, we hope to have maintained a satisfactory level of consistency across the work. We have also updated the genetics section as well as adding new explanatory sections on methods, longevity and epidemiology. We hope that these will give the interested reader some useful background on these topics as well as suggestions on where to find further information as required.

Companion animals are often bred according to the whims and needs of mankind rather than following the harsh survival rules of natural selection, and therefore breed‐related disease has become an important anthropogenic welfare issue. In consequence, it behoves everyone with an interest in companion animals to strive to reduce these animal welfare costs. A critical first step in this process is the need to define which breed–disease combinations (i.e. predispositions) have strong supporting evidence. We hope that the third edition of our book meets this need and provides a solid evidence base from which other companion animal stakeholders can develop effective strategies to improve animal welfare. Breeders and breeding organizations can use this book to identify priorities when considering the genetic health of their breeds. The show community, both those showing and those judging, may use this book to refine their opinions on optimal conformations and temperaments within individual breeds. The strong evidence‐based approach of the book can help veterinary students and veterinarians with diagnosis and when advising prospective and current owners on breed‐specific disease proclivities. Owners may find the book useful when deciding on breed selection or considering on how best to care for their current or prospective dog or cat. Ultimately, this book aims to enhance the welfare of current and future generations of cats and dogs by increasing our awareness of those diseases which commonly affect individual breeds and which may therefore be prevented or diagnosed earlier. Good evidence on breed predispositions empowers us all to combat disease occurrence and should lead to improvements in the lives of our dogs and cats.

We have thoroughly enjoyed writing this book: it became a labour of love for the three of us and consumed our lives for over a year, but we are very proud of the final product. There will obviously be some parts that we will re‐read later and decide we could have done better, and we welcome the reader letting us know about these. There will also be some opportunities that were missed in this edition, and we will be glad to receive suggestions. However, we hope you will forgive these shortcomings for now and simply accept this third edition for what it is: an evidence‐based blueprint for the current state of knowledge on breed predispositions to disease in dogs and cats. We hope you enjoy reading this book.

Alex Gough, Alison Thomas and Dan O’Neill

Abbreviations

95% CI

95% confidence interval

AKC

American Kennel Club

ANA

antinuclear antibodies

aPTT

activated partial thromboplastin time

AV

atrioventricular

CI

confidence interval

CYAR

cat years at risk

DYAR

dog years at risk

E. coli

Escherichia coli

EBVM

evidence‐based veterinary medicine

ECG

electrocardiography

GSD

German Shepherd Dog

Ig

immunoglobulin, including isotypes IgA, IgG and IgM

IR

incidence rate

IRR

incidence rate ratio

KC

Kennel Club

MHC

major histocompatibility complex

MRI

magnetic resonance imaging

OR

odds ratio

PCR

polymerase chain reaction

PR

prevalence ratio

PT

prothrombin time

RR

relative risk,

or

risk ratio

SBT

Staffordshire Bull Terrier

T

4

thyroxine

TRH

thyrotropin‐releasing hormone

TSH

thyroid‐stimulating hormone

VMDB

Veterinary Medical Database

WHWT

West Highland White Terrier

Introduction

BASIC AND CLINICAL GENETICS

Inherited diseases and breed predisposition

It has long been recognized that many traits, desirable and undesirable, can be passed along family lines. Darwin noted in 1868 that there is a ‘unanimity of … belief by veterinaries of all nations in the transmission of various morbid tendencies’. Inherited diseases in dogs and cats can be categorized as those associated with adherence to breed standards and those unrelated to breed standards. The brachycephalic head shape is particularly associated with a number of diseases such as brachycephalic obstructive airway syndrome, dystocia and corneal ulceration (Packer et al., 2015; O’Neill et al., 2017b, 2017c). Diseases not directly related to breed standards include many intraocular diseases, haematological and immune‐mediated diseases, and endocrine diseases (although the creation of small gene pools for a breed because of adherence to breed standards may have contributed to the prevalence of these diseases). For ease of use, the accounts in this book have been arranged by body system rather than in relation to breed standards.

It should be noted that while most conditions with breed predispositions are likely to be truly hereditary, this is not always the case. (Note that in our text, we use hereditary, genetic and inherited as synonyms.) Some conditions may arise because of the use to which the animal is commonly put, such as racing injuries in greyhounds, or to their behaviour, such as the searching behaviour of spaniels making them prone to grass awn (grass seed) foreign bodies. Nevertheless, even diseases such as these will have a genetic component, for example in influencing the behaviour of the spaniel, or giving the greyhound the athletic ability that means it is used for racing, and therefore can still be considered to have some inheritabilty.

Domestication and the canine and feline genome

Dogs are thought to be descended from a common ancestor with wolves, with estimates for the timing of the divergence ranging from 15 000 to 100 000 years ago. Domestication may have occurred more than once, and there may have been further interbreeding with wolves subsequently. At least two bottlenecks have occurred in canine genetic history, one when they diverged from wolves, and another more recently when modern dog breeds were created. Nevertheless, the dog has an enormous variation in phenotype, as shown by characteristics such as size, colour, coat type and behaviour.

It has been shown that there is more variation in functional genes in domestic dogs than in wolves (Cruz et al., 2008), and alterations in functional genes are often deleterious to welfare. Population bottlenecks and selective breeding may have exacerbated this, and natural selection against these deleterious conditions is less likely in domestic animals than in their wild counterparts. Domestic dogs may therefore be more prone to inherited diseases than wolves.

Dogs were originally bred to fulfil many different purposes, such as hunting, fighting, guarding, herding and companionship. Sighthound type hunting dogs have been noted in archaeological records dating back 4000 years, and in Ancient Roman times, Columella described the division of dog breeds into working and hunting types. However, most modern dog breeds originate in the last 150 years, with the development of dog breeding as a hobby of the middle‐ and upper‐class Victorian.

In a study (Parker et al., 2007) that examined the DNA of a large number of dogs representing 161 breeds, the authors were able to divide the breeds into ‘clades’, that is, breeds with common ancestors. This paper shows how complex the genetic history of the dog is, but certain interesting points stand out. One is that single mutations can cause recognizable changes across multiple breeds within a clade. This has the consequence that dogs in a single clade may be prone to similar inherited diseases. Since most dog breeds are young in evolutionary terms, there has been little time for new mutations to occur, and so most disease‐causing genetic mutations are thought to have occurred before the breeds were founded. It is also notable that related breeds came out of certain times and geographical locations. For example, dog fighting was popular in Ireland in the 1800s, and many mastiffs and bull terrier crosses from this location and period later developed into recognized breeds. The introduction of dogs into North America by European settlers and later Asian migrations largely replaced the indigenous domesticated canine population which had been introduced by the first American settlers over 10 000 years previously. However, this study showed that breeds related to animals brought by European settlers likely had some interbreeding with the more ancient American breeds, and so American breeds of European origin retain some of the genetic material of the previous indigenous breeds.

Phenotypic variation (e.g. conformation and behaviour) is much smaller in cats than in dogs. Cats are thought to have been domesticated later than dogs, but are probably of less direct use to humans as working animals than dogs, since they are harder to train. Deliberate breeding was therefore more limited, and domesticated cats show as much genetic diversity as the wildcat.

The canine and feline genomes have both been sequenced, and the body of research into the genome and into genetic diseases in these species is rapidly growing.

Basic genetics

All mammalian life is based on the genetic code stored within the nucleus of a cell. This genetic code is stored in a long molecule called deoxyribonucleic acid (DNA). Each DNA molecule is composed of a string of units, called bases. There are four different bases, and they attract each other in pairs – guanine to cytosine and adenine to thymine. When attached together, they form the famous double helix. The order in which these bases (or base pairs, since they always match together) occur along the molecule provides the code for the synthesis of proteins. Proteins are then responsible for most of the functions of the body, from the structure of tissues, to the biological catalysts called enzymes, to the hormones which regulate the body’s metabolic processes.

A length of DNA which codes for a particular protein is called a gene. Long strings of genes, interspersed with areas of DNA which do not code for proteins, make up chromosomes. Each nucleus of a mammalian cell contains a set number of chromosomes, except the sex cells (gametes) – sperm and ovum. For dogs this number is 78, and for cats it is 38.

When a somatic (body) cell divides, the chromosomes shorten and thicken within the nucleus, so they become visible under a microscope. They then replicate, and one copy of each chromosome separates into a new nucleus before the cell splits. This process is called mitosis. However, in the production of the gametes (the process of meiosis), the chromosomes line themselves up in the middle of the cell with a companion. This companion is always the same, and two chromosomes that associate together are called homologous pairs. These homologous pairs separate, so the gametes have half the number of chromosomes as normal cells. This means that when a sperm and ovum combine at fertilization, the newly formed cell (the zygote) has the correct number of chromosomes.

Homologous pairs code for related genes, but are not identical. The two genes, one on each chromosome, interact in different ways. Sometimes one gene is dominant to the other, the less dominant gene being termed recessive, and the expression of the gene, that is, the protein that is produced, will be determined by the dominant gene. In other cases both genes will play a role in the production of the protein, a situation called co‐dominance.

The exception to the homologous pairs are two chromosomes called the sex chromosomes (all the other chromosomes are called the autosomes). These chromosomes determine the sex of an animal. In most mammals, including dogs and cats (and humans), a female’s somatic cells contain two X chromosomes while the male’s somatic cells contain an X and a Y. At meiosis, the ova acquire a single X chromosome from the mother, whereas the sperm inherit either an X or a Y from the father. This has significance for the inheritance of conditions carried on the X chromosome, and means that some inherited diseases can be more prevalent in one sex than another.

Although any one animal will carry only up to two versions of a gene, many more can exist within a population because of mutation and natural selection. These different versions of the gene are called alleles.

In conditions and characteristics that are inherited in a simple way, that is, the conditions are autosomal dominant or recessive, a system of genetics devised by the monk Gregor Mendel (hence Mendelian genetics) can be used to predict the likely offspring of two parents, if the parents’ genetic make‐up is known. For example, the gene that codes for Labrador coat colours is dominant for black and recessive for brown. A Labrador with two alleles for black colour (call the allele B) is described as BB and hence the coat will be black. If it has one allele for black and one for brown (call the allele b), it will be described as Bb but the coat colour will still be black since this colour is dominant. However, if the dog possesses two alleles for brown (bb), it will be brown. The genetic make‐up is called the genotype, whereas the physical expression of the genes is called the phenotype.

The situation is slightly more complex when looking at matings, and a matrix can be used to aid prediction of offspring types. Take the example of a BB black male crossed with a bb brown female. The BB male will produce sperm each carrying a single B gene, and the female will produce ova each carrying a single b gene. These are then recombined at random to produce offspring. The matrix would therefore look like this:

This means that all the offspring would be Bb. They all carry the b gene for brown coat, but because this allele is recessive, the coat colour is black. An animal with two identical alleles (e.g. BB or bb) is called a homozygote, while an animal with two different alleles (e.g. Bb) is called a heterozygote. If a black Bb female were then crossed with a black Bb male a different pattern would emerge:

On average three of the offspring would be black: one a homozygote (BB) and two heterozygotes (Bb). The fourth would be a homozygote for brown coat colour (bb), and, since this b allele is not now being suppressed by the dominant B allele, the brown coat colour phenotype is expressed.

In fact, since the fertilization process is random, a litter of four pups may not be born in the exact 1:2:1 ratio, but if this were repeated enough times, the proportions of pups of the various genotypes would approximate to this.

Generally, the alleles separate randomly from each other. If a parent has two genetic conditions, just because one condition is expressed in an offspring, that does not mean that the other will be. However, some alleles that are closely positioned on a chromosome tend to be passed on together. Thus, two traits controlled by different genes may often be found together in the same individual, and the presence of one of these traits may act as a marker for the other. This process is known as linkage.

When one allele is not dominant over another co‐dominance exists. For example, certain flowers that have alleles for red flowers (R) and white flowers (W) will be coloured red if homozygous for red (RR), white if homozygous for white (WW) but pink if heterozygous (RW).

Some genes, even if dominant, do not always produce a physical effect in the host. For example, the condition polycystic kidney disease in cats is inherited as an autosomal dominant trait, but not all cats with the genes have cysts in their kidneys. This situation is called incomplete penetrance. Penetrance is the proportion of individuals with a particular genotype that demonstrate the characteristics normally expected with that genotype.

Some characteristics are carried on the X chromosome, and this can lead to the phenomenon of sex linkage. For example, Golden Retrievers are predisposed to a condition called X‐linked muscular dystrophy. The allele for muscular dystrophy (call it M) is carried on the X chromosome, as is the allele for a normal dog not suffering from the condition (call it N). M is recessive to N. Therefore a female carrying a single affected X chromosome (genetic make‐up XMXN) would not show the effects of the disease. If this female were mated with a normal male (XNY), then the matrix for their offspring would be as follows:

All of the females born to this cross will be clinically unaffected by the disease, but 50% of the females will be carriers of the disease. These will not show the disease, since they have a normal gene on the other X chromosome which suppresses the abnormal, recessive gene. However, the males only possess a single X chromosome, so the 50% of males born XMY will show the disease (since they do not possess another X chromosome with a normal gene). The 50% of males born XNY will not show the disease and will not carry it.

Because of this process, sex‐linked diseases usually affect only males, and males cannot normally be asymptomatic carriers. Females are often carriers, but the only way they can express the disease is if their mother was a carrier and their father was affected. This situation is rare in nature, especially for uncommon genes, but can occur in domestic animals due to inbreeding.

Some disease inheritances are more complex still, because more than one gene may determine the expression of a disease, or the interaction of genes and environment can determine the outcome in an individual. For example, more than one gene is considered to be responsible for hip dysplasia but the dog’s nutrition, exercise and other factors can also influence the severity of the disease.

Finally, some diseases are not inherited through the DNA of the cell nucleus at all, but through the DNA present within the mitochondria (which are intracellular organelles responsible for energy production). Mitochondria are entirely inherited from the mother, hence characteristics and diseases caused by mitochondrial DNA can only be passed down from the mother. Although conditions caused by mitochondrial DNA are rare, some canine myopathies are thought to be inherited this way.

In summary, an autosomal dominant trait is transmitted from generation to generation without skipping. Each affected offspring has at least one affected parent, unless the disease has arisen because of mutation. If the disease is lethal, then it will be very rare. An autosomal recessive disease may skip generations. If the two parents are affected, then all the offspring are affected. With an X‐linked dominant condition, affected males mated to normal females transmit the gene to their daughters, who are all affected, but not their sons. Affected females then pass the condition on to approximately half of their sons and half of their daughters. In the overall population, the incidence in females tends to be twice that of males. With an X‐linked recessive disease, the condition may skip generations. The incidence is more common in males. Affected males do not transmit the disease when mated to a normal female, but all female offspring will be carriers. Females showing the disease who are mated with normal males will pass the condition on to all their sons, and all their daughters will be carriers.

Clinical genetics

As noted above, genetic diseases may be more frequently encountered in domestic animals than in most wild populations. The process of domestication involves selecting animals for desirable traits from a human point of view. Initially, these traits would have been practical: speed in a horse, fertility and milk production in a cow, herding instincts in a sheepdog and so on. Over time, for animals such as dogs and cats that came to be kept for their companionship and aesthetic appeal, selection pressures switched towards features that made the animals fit in well to the human environment or made them look ‘cute’ – for example, miniaturization or achondroplasia – but which may have reduced adaptation to survive in the wild. As breeding practices were refined and the science of genetics was developed, inbreeding was used to create breeds that bred true with respect to certain desired characteristics (i.e. offspring greatly resembled their parents).

Unfortunately, inbreeding reduces the genetic variation within a breed, and tends to accentuate the expression of diseases that are due to recessive genes. Population bottlenecks occur through the importation of a small number of founder animals to a new country or because of regenerations of previously extinct breeds, and they are complicated by the popular sire effect whereby desirable individuals such as a show champion are overused (particularly males, which can produce many more offspring than a female). Most of the characterized genetic diseases of the dog are inherited as autosomal recessive traits. This may be because of inbreeding, but it is also due to the difficulty in identifying and eliminating recessive traits in breeding programmes.

It should be noted that inbreeding of itself does not cause genetic disease, and some degree of inbreeding can be of benefit for the concentration of desirable genes. In fact, some inbred strains of mice and rats are entirely homozygous and yet are quite healthy (Beck et al., 2000). Inbreeding promotes homozygosity, and thus deleterious recessive genes are exposed by increasing the probability of their expression. However, by exposing these genes, it is possible to eliminate them by further selective breeding.

Data are currently sparse regarding the prevalence of disease caused by the spontaneous appearance of new mutations. It seems likely that most of the genotypic variability of the domestic dog was present in its common ancestor with the wolf. However, it has been suggested that the Canidae family have elevated genome‐wide basal slippage rates, meaning an increased rate of creation of new mutations due to errors in replication, compared to humans and cats (Shearin & Ostrander 2010). In most of those limited cases studied, the mutation seems to be uniform within a breed. This suggests that a founder effect applies, that is, a single initial mutation was propagated throughout the breed. In some cases, closely related breeds may have the same mutation causing a disease – for example, phosphofructokinase deficiency in English Springers and American Cocker Spaniels (and presumably Sprockers) – suggesting that a common ancestor was responsible for the original mutation. Some diseases, however, have more than one mutation in the same gene (allelic heterogeneity) or mutations in different genes which can lead to the same outcome. For example, oculoskeletal dysplasia is caused by mutations of different genes in the Labrador and the Samoyed, while multifocal retinopathy is caused by two different mutations of the same gene (Guziewicz et al., 2007; Goldstein et al., 2010).

When determining whether a disease is heritable, certain typical characteristics increase suspicion of a genetic predisposition. Often the first thing to suggest that a disease is inherited is that the disease occurs with a higher frequency in a group of related animals than in the general population. This can help distinguish an inherited disease from a breed predisposition (although it can be argued that in most cases breed predispositions are related to genetics in some sense, and a breed predisposition is suggestive of a genetic cause). For example, St Bernards are predisposed to osteosarcomas (Egenvall et al., 2007), but it is possible this is merely a reflection of their large size, the faster growth rate leading to more mistakes being made in DNA replication, leading to cancer. However, analysis of pedigrees shows that there is a familial clustering pattern to cases of the disease, which suggests a specific gene or group of genes being responsible.

A hereditary defect often involves the same anatomic site in a group of related animals. This is often seen in congenital heart disease in dogs. Also, a hereditary disease is often seen to increase in frequency with inbreeding. Hereditary diseases often have an early onset, and those that do not often have a consistent age of onset. Hereditary diseases usually affect a few individuals within a litter, as opposed to intoxications and infectious diseases, which frequently affect higher proportions. Some genetic diseases will cause abortion or resorption, and these are often difficult to recognize clinically. Similarly, some hereditary diseases will cause a failure to thrive, the ‘fading kitten (or puppy) syndrome’, and again it can be hard to determine the cause in these cases.

There is an extremely wide range of severity of hereditary diseases, from the relatively benign to the invariably fatal. Diagnosis of a hereditary disease is usually based on history, clinical signs, history of disease in related individuals, test matings, specific imaging or clinicopathological tests for diseases and genetic testing.

Test matings are often suggested in order to identify autosomal recessive diseases, but this does have problems. With late‐onset defects, the results of the mating will be known too late to be useful in selecting which individuals to use for breeding. Test matings can be more useful for early‐onset diseases, but the ethics of keeping a known affected animal purely for test purposes, and what to do with affected offspring, can be problematic. Furthermore, the results of test matings may be unreliable. For example, in the case of a recessive disease in which the N allele is normal and n is abnormal, a mating of a suspected carrier (N?) to a known carrier (Nn) which produced six normal puppies would give only an 82.2% certainty that the N? was not a carrier (NN). However, a single abnormal pup would confirm carrier status.

The results of random matings, if performed often enough and with respect to a sufficiently prevalent gene, can provide useful information without the need to maintain a carrier or affected animal, and with less likelihood of breeding unwanted affected individuals.

Specific tests for diseases include ultrasonography and histopathology for polycystic kidney disease, MRI for syringomyelia, and von Willebrand factor assay for von Willebrand’s disease. Some laboratories will test samples using enzyme and immunological assays to detect diseases, and the results may indicate whether an individual is a homozygote or heterozygote. An example of this is testing for haemophilia B. A defect in an affected protein’s size, function or amount allows the identification of carriers of a disease in some cases, although there may be an overlap with normal values. Also, compensatory rises in other proteins, such as an isoenzyme related to pyruvate kinase in pyruvate kinase deficiency, may reduce the accuracy of this sort of test.

Causal molecular defects have been identified for some inherited diseases. Examples identified on the X chromosome include haemophilia B, severe combined X‐linked immunodeficiency and hereditary nephropathy. Some autosomal recessive traits for which the mutation has been identified include copper toxicosis in Bedlington Terriers, progressive retinal atrophy in Irish Setters, von Willebrand’s disease in Scottish Terriers and pyruvate kinase deficiency in Basenjis.

Many specific DNA tests are now commercially available to identify genetic diseases, and the number of tests is increasing rapidly, to include tests for such diverse diseases as degenerative myelopathy, von Willebrand’s disease, copper toxicosis and anal furunculosis.

Specific DNA test results for diseases should be interpreted with caution, and what may seem a clear‐cut result may often be misleading. For example, a positive genetic test result for degenerative myelopathy means the individual is at some risk for developing the disease. However, it does not mean that developing the disease is inevitable, nor does it mean that a clinically affected individual does not have another cause of its clinical signs, such as disc disease or neoplasia. Another pitfall is that there may be more than one type of mutation responsible for a disease, particularly between breeds. For example, the mutation causing muscular dystrophy in the Cavalier King Charles Spaniel is different from the one causing muscular dystrophy in the Golden Retriever.

DNA tests are either linkage‐based or mutation‐based. Linkage‐based tests look for a marker gene that is physically near the gene of interest. Mutation‐based tests look for the specific mutation causing a disease. Linkage tests may be inaccurate in a small number of cases where chromosomal recombination has occurred in the region between the marker and the mutation.

DNA testing shows great promise for the identification and elimination of genetic diseases in dogs and cats. The inherited diseases can be identified before an animal is bred, and affected animals can either be removed from the breeding pool or, in the case of recessive traits, bred only to normal individuals, to preserve desirable characteristics. This allows the genetic diversity of breeds to be retained while inherited diseases are eliminated.

The limitations of DNA testing, such as the limited availability of tests, and the fact that its utility is largely restricted to single‐gene diseases, mean that there is still a vital role for screening programmes to eliminate inherited diseases. Screening programmes currently in operation in the UK include the British Veterinary Association/Kennel Club programmes for hip and elbow dysplasia and eye diseases, and the International Cat Care scheme for polycystic kidney disease.

EPIDEMIOLOGY

The first and second editions of this book applied relatively loose evidence‐based approaches to report on predispositions to diseases in dogs and cats. These evidence‐based methods were not explicitly defined and were heavily reliant on expert opinion from textbooks, review articles and conference proceedings. Expert opinion is sometimes called ‘eminence‐based’ veterinary medicine; it represents the personal view of recognized experts or self‐appointed commentators without explicit external critical appraisal applied to its quality as evidence. Expert opinion is commonly promulgated as ‘evidence’ in veterinary medicine, particularly at conferences, in editorials and during undergraduate teaching. However, it is widely considered to be weak evidence at best, unless underpinned by a solid and stated evidential platform (Holmes, 2007). This is because many cognitive biases are inevitably inherent within the belief systems of any individual expert, which also explains why experts so often vehemently disagree on specific issues.

This third edition of Breed Predispositions to Disease in Dogs and Cats aims to be more explicit about how the epidemiological results for each breed–disease combination were chosen for inclusion. The book also aimed to cite those references that related to the highest available quality of study designs for each disease. Most of the references in this new book describe original research that has been published in high‐quality peer‐reviewed journals. To support our new emphasis on reporting quantitative results from primary research, we have penned this introduction to epidemiology, to explain the epidemiologic metrics (e.g. prevalence, odds) that are reported throughout the book. Further information on this fascinating science of epidemiology is available in several useful texts (Thrusfield, 2007; Dohoo et al., 2009; Pfeiffer, 2010).