Concerns for Offspring of Infertile Men Conceived by Intracytoplasmic Sperm Injection

Intracytoplasmic sperm injection (ICSI) used in combination with in vitro fertilization (ICSI) has allowed couples with otherwise untreatable infertility to become parents. Although follow-up of the first generation of ICSI conceived children provides some insight into the outcomes of the procedure, questions concerning the safety of ICSI persist. From a genetic viewpoint, infertile couples reflect the end of that gene pool and defective genes cannot be transmitted. Today with ICSI, this concept has changed. Deficient DNA repair, microsatellite instability and unstable androgen receptor trinucleotide repeats in infertile men lead us to hypothesize that infertile men are more likely to have unstable neurodegenerative disease-associated microsatellites repeat length for the Dystrophica Myotonica Protein Kinase (DMPK) gene and ataxin (ATXN) 1 and 2 genes than fertile men. These diseases are autosomal dominant neurodegenerative diseases that manifest in the third or fourth decade of life (earlier in severe cases). Trinucleotide allele lengths associated with myotonic dystrophy type I (DMPK) and the spinocerebellar ataxias types I and 2 (ATXN1 and 2) were measured in over 1500 infertile and control men evaluated in Houston, USA and Melbourne, Australia. A subset of infertile men had triplet repeat lengths in the mutable normal, reduced or full penetrance ranges for DMPK (≥35 repeats n=6) and ATXN2 (>31 repeats n=2) with about 1% of the infertile men tested in the Houston cohort expected to develop mild disease symptoms with aging. As unstable alleles are prone to expansion during spermatogenesis, assisted reproduction may transmit unstable neurodegenerative disease-associated alleles to the offspring. Indeed, we observed vertical transmission of DMPK and ataxin-2 as well as de-novo acquisition of unstable alleles resulting from the loss of interrupts in the paternal allele in the children of these men conceived by ICSI. Thus ICSI provides a novel mechanism for paternal transmission of these triplet repeat diseases raising concern for children conceived by this assisted reproductive technology.