Your Genes, Your Health A Critical Family Guide That Could
Save Your Life
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TO JEFF.
For the joy of being your Dad.
For the pride in your achievements.
For the admiration of you as a father.
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If, of all the words of tongue and pen,
The saddest are, “It might have been,”
More sad are these we daily see:
“It is, but hadn’t ought to be.”
— Francis Bret Harte
in “Mrs. Judge Jenkins”
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contents
Preface xi
Acknowledgments xv
1. Why and What You Should Know 3
2. Too Many or Too Few Chromosomes 14
3. X’s and Y’s: The Sex Chromosomes 26
4. Chromosome Rearrangements 39
5. Blueprints: You and Your Genes 50
6. How Genes are Transmitted 65
7. Prenatal Diagnosis 84
8. When Good Cells Go Wrong 105
9. Matters of the Heart 126
10. Consequences of Failure to Diagnose 141
11. Genes Gone Missing 151
12. Earlier and More Severe Genetic Disorders 164
13. The Determination to Have a Healthy Child 173
14. Irrevocability and Acceptance 183
15. Ancestral Genetic Burdens 193
16. Puzzling Fevers 213
17. Bleeding and Clotting 220
18. Blood Vessels that Burst 239
19. Brain Connections and Disconnections 250
20. Skin: A Mirror to the Brain 266
21. Genes with Signatures 275
22. Maternal Inheritance and Inevitability 283
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x Contents
23. Harmful Maternal Effects on the Fetus 288
24. Patterns of Anomalies 301
25. Treatment Options 311
26. Sugar and Metals 329
27. Obesity: A Weighty Burden 339
28. Hypertension 349
Frequently Asked Questions 359
Appendix 1: Cancer Susceptibility Syndromes for which Preimplantation
Genetic Diagnoses have been Performed 368
Appendix 2: Selected Single-Gene Disorders with Germline
Mosaicism 369
Appendix 3: Genetic Diseases in which Dynamic Mutations with
Triplet Repeat Expansions do Occur 371
Appendix 4: Selected Genetic Disorders with Anticipation or
Suspected Anticipation 372
Appendix 5: Guidelines for the Molecular Genetics Predictive Test in
Huntington Disease 374
Appendix 6: Genetic Disorders in which Dilatation of the
Aorta May Occur 377
Appendix 7: Examples Of Imprinting in Genetic Disorders 378
Appendix 8: Genetic Resources And Support Organizations 379
Index 381
preface
Have you ever read a book that could save your life or that of a loved one? This
might be it! If you harbor a particular gene mutation that was destined to cause
you serious illness, disability, or even death, and there were actions to take that
would enable you to avoid, prevent, ameliorate, or treat unwanted conse-
quences, wouldn’t you want to know? If you had children (or plan to have) or
living parents and the knowledge of this gene mutation would help them too,
wouldn’t you want to know? This book is dedicated to the proposition that you
would want to know and that to know is to care.
For most, recognition of risk is a prelude to action. Imagine you were cross-
ing a street and suddenly realized that an out-of-control truck was hurtling
toward you and that there was no escape. If you had been forewarned and had
spotted the truck before crossing the street, you could have taken evasive
action and avoided a catastrophe. Similarly, if you were standing on the street
corner watching a loved one cross the street and saw the truck bearing down,
would you not automatically yell out a warning? Silence and inaction are the
alternatives but can result in tragedy and loss, much as I have witnessed these
many decades seeing patients and families echoing what now is an all-to-fa-
miliar refrain—“If we had only known.”
Now, with the continuing resolution of the human genome, we have an enor-
mous amount of new information about our genes that enable us to avoid,
prevent, and treat an ever-increasing number of genetic disorders. We know
that our body structure and function result from the action of our genes with
some environmental influence. Indeed, every genetic and non-genetic disease
is influenced, caused, regulated, or modulated by our genes, as is our body’s
response to environmental factors such as viruses, bacteria, X-rays, tempera-
ture, diet, medications, carcinogens, and even trauma.
Gene discovery has revealed that you—indeed, all of us—unwittingly carry a
significant number of harmful genes that may remain hidden for a lifetime.
Many, however, eventually make their presence known in us or a loved one.
There are a large number of examples discussed in this book that include many
specific genetic disorders caused by single or multiple harmful genes that
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xii Preface
involve particular organs or systems. Manifestations wrought by these gene
mutations or variations include cancer, heart disease, birth defects, mental
retardation, infertility, recurrent miscarriage, diabetes, hypertension, obesity,
Alzheimer’s disease, depression, schizophrenia, epilepsy, drug actions and
reactions, as well as allergies. Gene mutations found especially (but not only)
in our ethnic or racial group are given special emphasis, as are the susceptibil-
ity genes that cause or contribute to the development of autism, and the
common disorders to which we all fall victim.
The first seven chapters help the reader establish a factual understanding of
chromosomes and genes, the various ways genetic disorders are transmitted
and the options for avoidance or prevention. Chapters that follow recount the
histories of many families whose experiences serve as important lessons. For
virtually all genetic disorders discussed, there is potential involvement in
reproduction, effects in children and adults, and options for avoidance, pre-
vention, and treatment. Hence, the family stories of disease and destiny, pain
and certainty, and the power of prediction all meld into life’s mosaic and are
not presented in a systematic categorical way. Placement of Chapter 25, (which
discusses treatment options) towards the end of the book is necessary if the
reader is to comprehend the vast range of genetic disorders for which thera-
peutic approaches now exist. The final three chapters represent very common
disorders overwhelmingly caused by the interaction of multiple genes and
environmental factors.
This book is not, however, an encyclopedia of genetic disorders. Realization
that our genomes are made up of more than 3 billion bits of DNA, that there
are almost 20,000 entries in the key genetic disorders database,1 and more than
21,500 recognized protein-coding genes (thus far) gives pause to any author.
Rather, my intention is to focus on patients and families my son2 and I have
seen in consultation. My purpose throughout is to share my long and extensive
experience and the lessons learned from those for whom I have had the privi-
lege of providing care. I have, of course, been careful not to divulge any clues
that enable recognition of any individual or family. Many will recognize a
genetic disorder in their families for the first time after reading this book. The
likely reason is that the vast majority of people with a genetic disorder have not
1. Called Online Mendelian Inheritance in Man
2. Jeff Milunsky, MD, Professor of Pediatrics and Genetics and Genomics, and Co-Director of
the Center for Human Genetics at Boston University School of Medicine
xiii Preface
consulted a clinical geneticist. If this book helps remedy that situation, lives
will be saved for some and health secured for many.
You need no prior knowledge of genetics or biology to understand the facts
and lessons outlined here. I have selected individual patients and families
whose histories, often poignant, help communicate quintessential facts and
messages over a wide range of genetic disorders. The emerging lessons can be
applied to many disorders in the same category, without discussing each in
turn. I have used italics to describe patients and families, shaded boxes for
commentary on the specific cases, and normal print to provide additional
factual and up-to-date information on the disorders discussed. The Index will
prove helpful in seeking information on a subject that is not confined to a
single chapter, and the Appendix provides a number of tables with more detail
about certain genetic disorders.
Reading about the families I describe with specific selected genetic disorders
will undoubtedly alert many to potential risks that they had never recognized
or known and to the important steps they now need to take. I have purpose-
fully not provided a detailed list of genetic disorders in the Table of Contents,
as that would inevitably lead the reader to familiar or special interest topics
and miss one of my main goals. Specifically, I hope that readers will recognize
for the first time that certain health issues in one or more family members, not
previously thought of as genetic, are directly pertinent to their lives and health.
You may also suddenly realize that the family of a close friend is unknowingly
at risk, and your action in drawing their attention to the information could be
life-saving.
I want to be sure that any idea you might have that your genetic destiny is pre-
ordained and that you can do nothing about it is forever dispelled. You should
know your three-generation family history where possible, be cognizant of your
ethnic origins, opt for indicated gene tests, take preventive actions, determine
your genetic susceptibilities, establish appropriate surveillance for you and your
loved ones, and seek pre-emptive treatment where possible. This book will
empower and encourage you to KNOW YOUR GENES, SECURE YOUR
HEALTH, AND HELP SAVE YOUR LIFE.
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acknowledgments
The information in this book represents a distillation of facts and concepts
published over many decades in thousands of scientific papers. It is with great
respect and awe that I acknowledge all the scientists and physicians whose
work I have admired and relied on. Facts and concepts are, however, insuffi-
cient in the practice of medicine. It is from the thousands of patients I have
seen that I learned the importance of humanity, empathy, and understanding
of the human condition. I acknowledge with gratitude and humility the les-
sons my patients have taught me these many decades.
In retrospect, I believe that I and my colleagues graduated from the University
of the Witwatersrand Medical School in Johannesburg, South Africa, during a
golden era of medical education. A remarkable number of graduates in those
years emigrated and achieved success in many countries. Dr. Gerald Gilchrist
in 2004 published his (informal) survey of South African academic pediatri-
cians in the United States and found 65 full professors of pediatrics in the
United States, all from our Medical School. This, of course, does not account
for the many others in similar positions in internal medicine, surgery, and
other specialties.
These successes were not the result of chance. We were fortunate in having
remarkable and outstanding basic science and clinical teachers. Although all
influenced my growth and development, there were a few whose imprint
molded my life in medicine and to whom I am eternally grateful.
Phillip V. Tobias, Dean and Professor of Anatomy, Emeritus, world-famous
anthropologist, and one of the world’s leading authorities on the evolution of
mankind. He was subsequently nominated for the Nobel Prize. He unwittingly
planted the idea of genetics in my head. It was from him that I first felt the
excitement of discovery from research well-done. His lectures were akin to a
symphony in words. He is one of the finest orators I have ever heard.
Sydney Brenner, then Lecturer in Physiology and later Nobel Prize winning
scientist, who became the head of the Medical Research Council Laboratory of
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xvi Acknowledgments
Molecular Biology (and later Molecular Genetics) in Cambridge, England. In
2000 he was appointed Distinguished Professor in the Salk Institute in La Jolla,
California. From him I later realized that I had learned to question and look
beyond the “obvious.”
D.J. DuPlessis, the late Dean and Professor of Surgery, for whom I worked as
a resident and who taught me the art of incisive and logical thinking so valu-
able at the bedside. By example, he conveyed the importance of discipline of
thought and action that have guided me through my life in medicine.
Solomon E. Levin, Professor of Pediatrics and a superb cardiologist who
taught me the basic and finer points of pediatrics and pediatric cardiology.
Even more important, he encouraged my nascent interest in research. My very
first two published papers were with him. He couldn’t have known that the
pleasure and pride of those papers powered my creative engine, resulting (thus
far) in more than 400 published scientific communications and 24 written and
edited books. By example, I learned from him humility, sensitivity, and the
benefits to a child of a gentle reassuring voice and hand.
Harry C. Seftel, Professor of Medicine, for whom I worked as a resident (and
Registrar in that system), who taught me that there were no limits to the acqui-
sition of knowledge. To this day, his encyclopedic knowledge of medicine has
left me feeling insufficiently knowledgeable, despite being board-certified as a
specialist in three separate disciplines (internal medicine, pediatrics, and med-
ical genetics). His diagnostic acumen remained as a beacon and a standard for
me to achieve in a lifetime of medicine.
While I could never have hoped to emulate the collective brilliance of my
teachers and mentors, I acknowledge with gratitude the limited abilities I
gleaned from their efforts. I do know that I have been a worthy carrier who has
also shared their passion for medicine and science.
My grateful appreciation is extended to Seema Jamal, M.Sc., LGC, CCGC,
one of our outstanding genetic counselors, who read the entire manuscript
and made important recommendations. Multiple iterations of the manuscript
were made possible only through the superlative efforts of Sheila Kelly, Jessica
Storozuk, and Marilyn McPhail. Thanks, too, are extended to my wife Laura,
for her love, support, understanding, and fruitful discussion.
Your Genes, Your Health
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