Inheritance: How Our Genes Change Our Lives--and Our Lives Change Our Genes

by Moalem MD PhD, Sharon

  As I continued to study Susan’s features, I had a significant ethical dilemma on my hands. The host and other guests were certainly not my patients, and they surely hadn’t invited me to diagnose any possible genetic or congenital conditions they might have. This was a woman I’d only just met. How would I broach the subject? Or stop myself from blurting out that her distinctive appearance—her eyes, her nose, her lips, and possibly a trademark stretch of skin connecting her neck and shoulders, called a webbed neck—made it quite likely that she had a genetic condition. Besides having implications for any future children, Noonan syndrome is also associated with potential heart disease, learning disabilities, impaired blood clotting, and other troubling symptoms.

  Noonan syndrome is just one of many so-called “hidden conditions,” since the associated traits aren’t all that unusual. As with the extra row of eyelashes, it’s not uncommon for people to be unaware that they have it until they start looking for it. It wasn’t as though I could simply walk up to her and say, “Thank you for inviting us for dinner. The tempeh was delicious. By the way, did you know that you have a potentially deadly autosomal dominant disorder?”

  Instead, I decided to just ask if there were wedding pictures around. I thought this might help clarify for me if she really had Noonan syndrome, which is generally inherited from an affected parent. After the second photo album and umpteenth picture of the bride with her mother, it was clear that they shared many of the same physical characteristics.

  “Yup,” I thought. “Noonan it is.”

  “Wow,” I said, going in for what I hoped would be a soft broaching of the subject. “You really look like your mother.”

  “Yes, I get that often,” was her first response. “Actually, your wife told me a little bit about what you do…”

  At that exact moment I really wasn’t sure in which direction the conversation was headed. Mercifully, Susan came to my rescue.

  “My mother and I have this genetic condition, it’s called Noonan syndrome, have you heard of it?”

  As it turns out, Susan was well aware of her condition, though few others were. And friends at the party, who had known her much longer than I, marveled at how I’d been able to diagnose her condition based on slight physical differences they’d hardly noticed.

  The truth is, though, that it doesn’t take a physician to do this sort of thing. Everybody does it. You did it the last time you saw someone with Down syndrome. You might not have thought about it as your eyes surveyed the hallmark attributes—upslanting palpebral fissures, short arms and fingers (called brachydactyly), low-set ears, a flat nasal bridge—but you were conducting a rapid genetic diagnosis. Having seen enough cases of Down syndrome over your lifetime you unknowingly ran through a mental checklist of features to arrive at a medical conclusion.8

  We can do this with thousands of conditions. The better we get at it, the tougher it is to stop doing it. It can be annoying (as understandably it sometimes is to my wife), and it might wreck a dinner party, but it’s also important—because sometimes a person’s appearance is the only way to determine that they have a genetic or congenital disorder. Sometimes, believe it or not, as you’ll see in a moment, we just don’t have any other reliable test.

  Go back again and take a look at the area between your nose and upper lip. Those two vertical lines demarcate your philtrum, and this happens to be the site where, during early development, several pieces of tissue migrated and met, like great continental shelves crashing together to form a mountain range.

  Do you remember what I said about our faces being a lot like a Louis Vuitton logo—a sign of our genetic quality and developmental history? Now, if you’re having trouble seeing the lines of your philtrum and the area is somewhat smooth, and if your eyes are a bit small or spread apart, and if you’ve got an upturned nose, too, then your mother may have been drinking while she was pregnant with you, creating a perfect storm of exposure called fetal alcohol spectrum disorder, or FASD. We tend to hear these words together and cringe, because FASD is commonly thought to be a devastating cluster of disorders. It can be. But it can also be mildly expressed, sometimes with just a few physical facial clues and little else as a result. In spite of all the amazing breakthroughs in medicine and genetics that we’ve experienced over the past decade, there’s still no definitive test for it other than the same visual inspection that you just performed on yourself.9

  That brings us back to your hand. Now that you have an idea of how specific traits and the combinations of those traits can provide information about someone’s genetic makeup, you can look at your hand the way I would. Take a look at the lines on your palms. How many major creases do you have? I have a big curved one running opposite my thumb, and then two creases running horizontally below my fingers.

  Do you have a single crease running along your palm, below your fingers? This can be associated with FASD and Trisomy 21, but rest assured because around 10 percent of the population has at least one hand with one abnormality and no other indicators of genetic disease.

  What about your fingers? Are your fingers excessively long? If so, you might have arachnodactyly,* a condition of long fingers that can be associated with Marfan syndrome and other genetic disorders.

  And as long as we’re looking at your fingers, do they taper toward your nails? Are your nail beds deep set? Now have a good look at your pinkies. Are they straight, or do they curve inward toward the rest of your fingers? If they do have a distinctive curve, you might have something called clinodactyly, which can be associated with more than 60 syndromes, or be isolated and completely benign.

  Don’t forget your thumbs. Are they wide? Do they look like your big toes? If so, that’s called brachydactyly type D, and if you’ve got it, you’re in an inheritance club that includes the actor Megan Fox, although you wouldn’t know it based on Motorola’s 2010 Super Bowl advertisement in which she starred, because the directors used a thumb double.10 It can also be a symptom of Hirschsprung’s disease, a condition that can affect the way your intestines work.

  You may want a little privacy for this next examination. If you’re reading this book at home or somewhere else where you don’t feel self-conscious, slip off your shoes and socks and gently pull apart your second and third toes. If you find that there’s an extra little flap of skin there, then you likely carry a variation in the long arm of your chromosome 2 that is associated with a condition called syndactyly type 1.11

  We all start out, during the first stages of our development, with hands that have the appearance of baseball gloves. But as we develop we lose the webbing between our fingers as our genes help instruct the skin cells between our fingers and toes to die off.

  Sometimes, though, the cells refuse to go. On our hands and feet, that’s usually not the end of the world; surgery can generally fix the rare cases of syndactyly that are debilitating—and lots of people have started to get creative with extra skin between their toes, using tattoos and piercings to call hipster-like attention to a little bit of extra epidermal terrain that most people don’t have.

  If you have a child with this condition who isn’t yet old enough for body art, you could always tell them it might just make them a better swimmer. That’s the case for ducks, of course. Ducks use their webbed feet to balance and paddle along when in the water and to thrust themselves, jet-like, when they’re below the surface looking for food.

  How do ducks keep their feet webbed? The tissue between their digits survives thanks to the expression of a protein called Gremlin, which behaves a little like a cellular crisis counselor, convincing the cells between a duck’s toes not to kill themselves, as they would in most other species of birds and people alike. Without Gremlin, it seems, ducks would have feet like chickens. And that wouldn’t do them much good in the water.

  Now, can you bend your thumb to touch your wrist? Can you bend your pinkie back beyond 90 degrees? If so, you might have one of a very common and underdiagnosed group of conditions called Ehlers-Danlos
syndrome. And you may need to start taking a medication called an angiotensin II receptor blocker, which is currently under clinical investigation, to keep your aorta from dissecting (or shredding). That sounds dramatic, but yes, it’s true: From a simple evaluation of your hands, you can tell if you’re at increased risk of cardiovascular complications.

  That’s how some physicians use genetics to inform their practice. Yes, sometimes we employ high-tech tools to take a look at your genetic mural. Sometimes we stay up late at night studying your genetic sequence on an online database, like a computer programmer trying to debug a complicated piece of code. But quite often we use a combination of very low-tech techniques to diagnose conditions. And sometimes it’s a combination of simple, subtle clues with high-tech analysis that tells us what we most need to know about what’s going on deep and small inside of you.

  What does this look like in practice? Well, before I even lay eyes on a patient, I’m usually given a referral slip from another physician. On a good day, I get a detailed letter explaining why that physician would like me to see their patient and what specific concerns they might have. Sometimes they proffer a very educated guess.

  And often not.

  Usually, I’m starting with short, vague terms like “developmental delay.” Other times I get a message like “hirsutism or multiple pigmented patches on skin, along the lines of Blaschko.” Yes, over the years computers have eliminated the challenge of deciphering physicians’ notoriously bad handwriting, but we still seem to pride ourselves on using complicated and esoteric language.

  Of course, it could be worse: In the past, some physicians would note in the chart or referral F.L.K., which inappropriately meant “funny-looking kid.” This was medical shorthand for “I’m not quite sure what’s wrong, but something just doesn’t look right.” For the most part, those initials have been replaced with the more scientific, accurate, and compassionate word dysmorphic. But that’s still a vague description.

  It only takes a few short words to send my mind racing. Even before I see a patient who has been described to me as dysmorphic, I begin running through all the algorithms I’ve internalized and start thinking about the important things I need to remember to ask the patient and their family. I consider what few clues I already have. A patient’s name sometimes gives hints of ethnic background, an important factor in many genetic diseases—and since some cultures have long histories of intrafamily marriages, names can also clue me in to the possibility of the patient’s parents being related.12 An age tells me where someone might be in the development of his or her condition. And the department from which the referral comes gives me a clue as to what the most obvious or pressing symptoms of the patient’s condition might be.

  This, for me, is stage 1.

  Stage 2 starts as soon as I enter the examination room. You might have heard that people in charge of reviewing applicants for a new job gain a tremendous amount of information about a candidate within the first few seconds of meeting. The same goes for doctors. Almost immediately, I begin to deconstruct my patient’s face, much like you examined your own face in the mirror. I look at the patient’s eyes, nose, philtrum, mouth, chin, and a few other landmarks and then try to rearrange them, putting them back together piece by piece. Before I ask a patient anything at all, I ask myself, how is this person different?

  Dysmorphology is a relatively young field of study that uses the parts of the face, hands, feet, and rest of the body to give us clues about an individual’s genetic inheritance. Disciples of this field try to identify physical clues that reveal the presence of an inherited or transmitted condition, not unlike art experts who employ knowledge and tools to determine the authenticity of a painting or sculpture.13

  Dysmorphology is also the first tool I retrieve from my toolbox when I’m meeting new patients. But of course, that’s not where it ends. Before I’m done, I’m going to want to know a lot more about you.

  That makes me a little bit different from most physicians. You see, a lot of your doctors get to know parts of you. Your cardiologist gets to see your heart in all its blood-pumping glory. Your allergist might know how you fare against pollens, environmental pollutants, and other personal poisons. Orthopedists take care of your crucial bones. Podiatrists are there for your precious feet.

  But as your physician with a special interest in genetics, I’m going to see a lot more of you. I’m going to have a look at every part. Every curve. Every crevice. Every bruise. And every secret.

  Locked away inside the nucleus of your cells is an encyclopedia about who you are, where you’ve been—and a whole bunch of clues as to where you’re going. And sure, some of the locks are going to be easier to pick than others, but it’s all there.

  You just need to know where and how to look.

  * It’s not only fructose that’s a problem but sucrose and sorbitol (which are converted to fructose in the body) as well. The latter is usually found in products such as “sugar-free” chewing gum.

  * We’ll discuss this concept in far greater depth in chapter 6.

  ** Because we’re medically unsure of the clinical outcomes of some of these changes, we call some of these differences variants of unknown significance.

  * Also called spider fingers.

  Chapter 2

  When Genes Misbehave

  What Apple, Costco, and a Danish Sperm Donor Teach Us about Genetic Expression

  In the modern world of classic genetics, Ralph is Mendel’s pea.

  For several years, the prodigious Danish sperm donor was a sought-after provider of the basic genetic elements that would, when paired with the genetic material of eager mothers across the globe, produce a rather predictable number of tall, strapping, and fair-haired children.

  And for a while, it seemed, everyone wanted a piece of that action.

  At 500 Danish kroner per sample (about $85 USD), a lot of young men with the right stuff (generally a combination of desirable physical and intellectual characteristics coupled with a high sperm count) have turned to semen donation to help make ends meet in Denmark, where tolerant social attitudes and Viking allure have made human semen a popular export.1

  But even by Scandinavian standards, Ralph was downright prolific.

  Owing to concerns that unwitting siblings might accidentally meet up—and hook up—somewhere down the road, donors like Ralph were supposed to stop providing semen after siring 25 children. But no one seemed to have figured out how to know when someone’s limit had been reached. And Ralph—whose dossier photo featured him riding a three-wheeled bicycle wearing Adidas shorts and a red vest—was so popular that, when he stopped donating of his own accord, some prospective parents, fixedly desirous of his genes, took to Internet message boards seeking to procure extra vials of his frozen semen.

  Ultimately, the man known to most of his recipients only as Donor 7042 would become the biological father of at least 43 children in several nations.

  As it turned out, though, Ralph wasn’t just sowing his Nordic oats. He was unknowingly spreading a bad seed—passing along a gene that causes excess body tissue to develop with sometimes disconcerting and life-altering results, including enormous sacks of sagging skin, profound facial deformities, and growths that can resemble deep-red, body-covering boils. The tumor-producing disorder, called neurofibromatosis type 1, or NF1, can also cause learning difficulties, blindness, and epilepsy.

  The story of Donor 7042 and his unfortunate offspring captivated public attention and resulted in swift changes to Danish laws governing the number of children who can be fathered by sperm donors.2 But for some families it was too little, too late.

  DNA had been passed. Babies had been made. Genes had been inherited. The principles first established by Gregor Mendel, the father of modern genetics, back in the mid-1800s, were alive and not so well in the twenty-first century.

  So why then were Ralph’s offspring afflicted with a disease from which he didn’t seem to suffer?

  Gregor Mendel was
n’t all that interested in peas. Not at first, at least. Instead, the inquisitive young monk wanted to experiment on mice.

  It took a dour old man named Anton Ernst Schaffgotsch to change Mendel’s direction—and in doing so, Schaffgotsch changed history.

  You see, if you were a monk with your eyes set on artistic endeavors or scientific discovery back in Mendel’s day, you could do no better than a calling to the humble hillside monastery of St. Thomas in the city of Brünn, in what is now the Czech Republic.

  The monks of St. Tom’s had long been a roguish bunch of reverends. Sure, they were always mindful that their primary responsibilities lay in service to their Lord, but within the confines of the abbey’s crumbling brick walls they’d developed a collegial culture of inquiry. Alongside prayer there was philosophy. Alongside meditation there was mathematics. There was music, art, and poetry.

  And, of course, there was science.

  Even today, their collective discoveries, insightful visions, and raucous debates would give church leaders a good case of heartburn. During the long, authoritarian reign of Pope Pius IX, however, their collective exploits were downright subversive. And Bishop Schaffgotsch was not amused.

  In fact, he had only tolerated the abbey’s extracurricular activity, Mendel’s journals indicate, because he didn’t understand much of it.

  Initially, Mendel’s work on the mating habits of mice seemed simple enough. But eventually, to Schaffgotsch, it simply went too far.3 For starters, the caged rodents in Mendel’s spacious, stone-floored quarters gave off a stench that Schaffgotsch found incompatible with the tidy life expected of a monk of the Augustinian order.