One area that causes frequent misunderstanding is the phenomenon of germ line mosaicism.
Here's a typical question (actually a composite of several queries to "Ask the Experts"):
Five years ago, I gave birth to a child with Duchenne muscular dystrophy (DMD). At that time, they tested my blood cell DNA and said I didn't have the deletion in my dystrophin genes that causes DMD. My son, Danny, does have a deletion.
The genetic counselor told me that, even though I'm not a regular carrier — by the blood DNA test — I still have a higher risk of having a second or third child with DMD than the average person. She also said my daughters had a higher than average risk of being carriers. Why is this?
W.T., Bangor, Maine
A different type of inheritance
The genetic counselor was telling W.T. that she may have germ line mosaicism with regard to her dystrophin genes. This is a way in which a mother or father can pass along a genetic flaw to a child, even though typical DNA tests show the parent isn't a carrier.
Here's how it happens:
Very early in the development of a baby in the womb (when it's still referred to as an embryo), cells that are the ancestors of the child's future sperm or egg cells separate from the rest of the developing embryo. Since sperm and egg cells are known as germ cells (from the Latin word germen, for "bud" or "embryo"), this batch of cells that's set aside is called the germ line.
As the embryo develops into a fetus, and continuing after the child's birth, the germ line cells divide and multiply. For boys, sperm cells don't complete their development until the child becomes an adolescent. A girl's egg cells complete part of their development during fetal life and part at puberty.
At any stage — from embryonic life through puberty or even later — mutations (changes) in the genes in the germ cells can occur. If mutations occur early, they affect many "offspring" (new sperm or egg cells) of the early germ cells. If they occur late, they affect very few, or maybe even just one, cell.
When germ line mutations occur, they rarely affect other cells in the body, because the germ line was segregated from the other body cells early in embryonic life. When mutations occur after the germ line has separated, there's a good chance they'll affect many sperm or egg cells but not any other cells, such as blood or skin cells, which are used in genetic testing.
The condition of having some germ cells affected and some not is called germ line or germinal mosaicism, derived from the idea of a mosaic pattern. (Picture, for example, a mosaic of blue and white tiles to represent affected and unaffected cells.) Another term is gonadal mosaicism, since the ovaries and testes, where eggs and sperm reside, are gonads.
If a child is conceived with one of the germ cells carrying a mutation, the child can inherit a disease-causing gene flaw, even though blood DNA tests in the parents won't show any flaw.
Predictions and odds
W.T.'s counselor is telling her that she may be a germ line mosaic and she can't assume that her negative DNA test, based on analysis of blood cells, proves that Danny's dystrophin mutation was a one-time event. It may have been, but it may not have been.
W.T.'s future daughters run a greater than average risk of being carriers of a dystrophin mutation, since W.T.'s possible germ line mosaicism could transmit a dystrophin mutation fairly often.
It isn't possible to get an accurate test of whether a man or woman is a germ line carrier for a particular disease because there's no way to test a representative sample of someone's sperm or egg cells. Even if a sample of germ cells shows no mutations, other germ cells still may have the mutation. Nor can tests show what percentage of a person's germ cells has a flaw.
Once a flawed gene has been introduced into the family from the germ lines, it becomes part of the inheritor's blood DNA and germ line DNA (as well as part of all other cells) and can be passed on to future generations.
DMD and other diseases
Men, as well as women, can be germ line mosaics, and Duchenne dystrophy isn't the only disease in which germ line mosaicism is a factor. However, this phenomenon has been particularly well studied in women who've had more than one child with DMD despite showing no dystrophin mutations in their blood cell DNA tests.
In one small study, six out of 41 mothers of boys with DMD whose blood cells showed no dystrophin mutation went on to have second sons with DMD, presumably because of germ line mosaicism.
For further reading, see MDA's booklet "Genetics and Neuromuscular Diseases." For specific information about your family, see a medical geneticist or genetic counselor through your local MDA clinic.
"Simply Stated" is a Quest column designed to explain some terms and basic facts about neuromuscular disease.