Long odds

I am by nature a conservative person, not much of a risk taker. Yet in life we take risks all the time, even if we don’t know it. We take a chance in just crossing the street or driving to work. How great is the risk that something terrible will happen to us as a result? Very small, as we all know, or we’d never walk out of the door in the morning. We may even buy a lottery ticket (academic salaries being what they are), even though we realize that we are almost certainly wasting our money. In the California lottery, there’s a pretty small chance of winning. To win a prize of any size requires correctly selecting five of six randomly chosen numbers between 1 and 51; the odds of doing this are only about 1 in 67,000. Recently I asked a good friend if he would accept the bet that there was a 1 in 30,000 chance that he would die tomorrow. “Yes. Every day of my life — those are really long odds,” he replied. And, after all, how often do we expect to win the lottery? But I didn’t ask him this question because I was interested in his expectation of winning the lottery. I asked because there is a genetic disorder called Cornelia de Lange Syndrome (CdLS), which occurs at about this frequency (1 in 20,000 to 1 in 40,000) of live births. Children with CdLS have a wide range of physical and mental problems with varying degrees of severity, including growth retardation, limb abnormalities, kidney problems, defects of the digestive system, speech disorders, hearing loss and mental retardation. Many children with CdLS live into adulthood, but some live one or two years, and some live only weeks or months. How do I know all this about such an obscure syndrome (raise your hand, everyone who has heard of CdLS)? I know because I had a daughter with CdLS. She had several of the rarer and more severe manifestations of the syndrome (which were undetectable prenatally despite all possible technology), and lived only 31 days. Current wisdom (such as it is) says that CdLS results from a dominant mutation in an unknown autosomal gene. The mutation is thought to arise most often in the gametes of an unaffected individual, as cases of vertical transmission are extremely rare. Parents with one affected child have an increased chance — about 1 in 50 — of having a second child with CdLS. This has led to the hypothesis that there is mosaicism in the germline of some transmitting parents, with some fraction of that individual’s gametes harboring the mutation and the rest being normal.