June 30, 1999
Fathers Pass Infertility to Sons
Researchers have discovered that sons conceived with the aid of a
popular in vitro fertilization technique can inherit the same
genetic defects that rendered their fathers infertile.
HHMI investigator David
Page of the Whitehead Institute for Biomedical Research at
Massachusetts Institute of Technology and his colleagues studied three
men who fathered sons through a widely used fertilization technique
called intracytoplasmic sperm injection (ICSI). In each case, the
fathers passed on a Y chromosome genetic defect called an AZFc
deletion. Such deletions are the most frequent molecularly defined
cause of failure to produce sperm, affecting about five to ten percent
of infertile men with insufficient sperm production. The research was
published in the July issue of the journal Human
Reproduction.
“Now we have four families, including the one in Taiwan, in which there are
boys who in all likelihood will be infertile as adults.”
David C. Page
Page also noted that researchers in Taiwan published an article in
the June issue of the journal Fertility and Sterility that
describes another family in which a son conceived by ICSI inherited the
AZFc defect from his father.
In treating AZFc-deficient men with ICSI, clinicians isolate the few
sperm that are produced and inject a single sperm directly into an egg.
The fertilized egg is then implanted in the mother.
While fertility experts had strongly suspected that the AZFc
deletion could be inherited in such cases, that suspicion had not been
clinically confirmed until now. The finding raises thorny ethical
questions about assisted reproduction techniques. "I think this finding
is going to change genetic counseling," said Page, "because what had
been a theoretical concern is now concrete. Now we have four families,
including the one in Taiwan, in which there are boys who in all
likelihood will be infertile as adults." (Girls are unaffected by the
defect, since they receive an X chromosome, rather than the defective Y
chromosome, from their fathers.)
Despite knowing about the defect and its inheritance pattern,
couples might not be deterred from trying to have sons, said Page.
"I am told by clinicians with whom I collaborate that most of the
couples they treat would simply wish to go ahead with having children
via ICSI. Some, in contrast, might elect to avoid transmitting the
infertility by using donor sperm or by adopting, and others could
decide to have only daughters by genetically testing the fertilized
embryos to determine their sex and only having female embryos
implanted, " said Page.
Page cautioned that genetic engineering of sperm to correct the
defect is still a farfetched notion "because, of course, any such
attempt at gene repair would carry with it the potential for collateral
damage."
A more likely remedy, says Page, is the possibility that affected
males, who may produce normal amounts of sperm during puberty and young
adulthood, may decide to have their sperm harvested for future use. To
date, however, scientists have not conducted careful clinical studies
to explore the link between changing sperm counts and age, he said.
"We only know now that men in their twenties and thirties with AZFc
deletions can have considerable variability in the number of sperm in
their semen." If sperm counts do prove to be higher in younger affected
males, said Page, they might have their sperm harvested and stored
until they are ready to start a family.
The latest findings emphasize the importance of basic research in
understanding the mechanisms by which Y chromosome deletions cause
infertility, said Page. "We really don't know why this missing piece of
the Y chromosome leads to spermatogenic failure, but we are learning
more and more about the missing genes," he said.
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