ICSI Fathers May Transmit Genetic Disease Risk


SAN DIEGO — Infertile men undergoing intracytoplasmic sperm injection display an elevated rate of genetic variations that may predispose them to pass on traits associated with neurodegenerative diseases, according to a study presented at the annual meeting of the Endocrine Society.

“This technique overcomes tremendous genetic barriers to reproduction and allows men with genetic disorders to achieve a pregnancy. It is therefore our concern that they will transmit these diseases to offspring,” said Francesca Gordon, a research associate at Baylor College of Medicine, Houston.

Ms. Gordon, Dolores J. Lamb, Ph.D., and their associates at Baylor and Monash Medical Center, Melbourne, obtained DNA samples from 647 infertile men whose partners were undergoing in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) in Houston and Melbourne and 369 normal controls from the same cities.

Polymerase chain reaction was used to analyze the lengths of triplet repeat tracts, also known as microsatellites, for three alleles associated with neurodegenerative disease: spinocerebral ataxia type 1 (SCA1), spinocerebral ataxia type 2 (SCA2), and dystrophia myotonica.

Several triplet repeat diseases such as Kennedy syndrome and myotonic dystrophy are associated with infertility.

The researchers hypothesized that expanded (normal, but unstable) microsatellite lengths associated with other triplet repeat diseases might be more common in infertile men, potentially putting at risk their children conceived through ICSI.

Ms. Gordon explained that there is a spectrum of repeat triplet lengths for each allele, ranging from normal to expanded-normal—a pattern that might pose a “pool of instability for future generations”—to a long expanse of triplet repeat tracks, associated with the development of symptoms. The length of the repeat correlates with disease severity and the age of onset. In general, the longer the triple repeat, the more severe the illness and the earlier symptoms occur.

There was a significantly increased incidence of unstable alleles associated with dystrophia myotonica in infertile men in Houston and Melbourne, compared with study controls.

Infertile men in Houston had an elevated incidence of unstable SCA2 alleles, compared with fertile control men. Conversely, only the men in Melbourne had a significantly elevated incidence of unstable SCA1 alleles, when compared with men in the control group.

Several of the patients exhibited repeat lengths in the mild to moderate disease range, whereas none of the control men did. The incidence of these unstable alleles varies by ethnicity and region, with SCA1 being more common in the general Australian population.

The incidence of dystrophia myotonica in the general population is estimated to be 5 in 100,000 people (0.00005%).

Infertile men in Houston had evidence of increased incidence of mild disease alleles, compared with men in the general population.

The estimated incidences of SCA1 and SCA2 are 0.006% in the general population.

Infertile men from both Houston and Melbourne had a higher incidence of SCA2 disease alleles than normal control samples. SCA1 disease alleles, in contrast, were increased, compared with controls only in the Melbourne population.

These results indicate there may be an increased risk of microsatellite expansion in infertile men using ICSI to father children. These men could then transmit these expanded alleles to their children, resulting in an increased risk of microsatellite expansion of neurodegenerative disease alleles in these individuals as well.

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