Interesting suggestions about Yq deletions

Abstract

Letter to the Editor: We read with interest the article by Feng and colleagues (1Feng C. Wang L.Q. Dong M.Y. Huang H.F. Assisted reproductive technology may increase clinical mutation detection in male offspring.Fertil Steril. 2008; 90: 92-96Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar) on a possible increased risk of microdeletions of the long arm of Y chromosome (Yq) occurring after fertilization in children conceived through assisted reproductive technology (ART). Although we consider indispensable carrying out rigorous scientific studies focused on the potential genetic and epigenetic risks of ART, we would like to make some comments on this article. First, an alternative explanation to that proposed by the investigators is that one or more fathers could carry the microdeletion in a mosaic fashion in the gonads. A mosaicism involving both somatic and germ-line cells or a confined gonadal mosaicism could clearly explain the reported normal spermatogenesis. However, it should be noted that in the article the sperm concentration of the four men who fathered the children with Yq microdeletions was not specified. Another hypothesis is that one or more of the Yq microdeletions observed in the ART-conceived children could arise from de novo random meiotic errors in paternal germ cell lineages. In addition, it should be underlined that in the article there is no mention of a DNA test to confirm the paternity of the children with microdeletions. We suggest performing the Yq microdeletion assay directly on the DNA extracted from the sperm of the four fathers (2Dada R. Kumar R. Shamsi M.B. Kumar R. Kucheria K. Sharma R.K. et al.Higher frequency of Yq microdeletions in sperm DNA as compared to DNA isolated from blood.Asian J Androl. 2007; 9: 720-722Crossref PubMed Scopus (20) Google Scholar, 3Hellani A. Al-Hassan S. Al-Duraihim A. Coskun S. Y chromosome microdeletions: are they implicated in teratozoospermia?.Hum Reprod. 2005; 20: 3505-3509Crossref PubMed Scopus (7) Google Scholar). Single-cell polymerase chain reaction (PCR) performed on DNA extracted from single spermatozoa, although time consuming, is an ideal method to enhance the probability of providing unequivocal proof of Yq microdeletion mosaicisms (3Hellani A. Al-Hassan S. Al-Duraihim A. Coskun S. Y chromosome microdeletions: are they implicated in teratozoospermia?.Hum Reprod. 2005; 20: 3505-3509Crossref PubMed Scopus (7) Google Scholar). Fluorescent in situ hybridization is another tool, which has been proved to be effective in detecting the presence of specific Yq microdeletion mosaicisms in germinal cells (4Le Bourhis C. Siffroi J.P. McElreavey K. Dadoune J.P. Y chromosome microdeletions and germinal mosaicism in infertile males.Mol Hum Reprod. 2000; 6: 688-693Crossref PubMed Scopus (30) Google Scholar). Finally, to confirm paternity, we suggest performing the DNA typing in all four father/baby pairs. However, although it is well known that the Y chromosome has a natural propensity for spontaneous deletion of DNA sequences, the incidence of de novo Yq microdeletions observed in the study by Feng et al. appears excessively high. For example, in a study conducted on a larger sample than that one of Feng et al., no de novo Yq microdeletions were detected in children conceived through intracytoplasmic sperm injection (ICSI) (5Cram D.S. Ma K. Bhasin S. Arias J. Pandjaitan M. Chu B. et al.Y chromosome analysis of infertile men and their sons conceived through intracytoplasmic sperm injection: vertical transmission of deletions and rarity of de novo deletions.Fertil Steril. 2000; 74: 909-915Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). These data lead to the suspicion of possible bias resulting from the small size of the study sample. Second, we believe that a single case with Yq microdeletion and hypospadia is not enough to take into consideration the existence of a causal relation between these two anomalies. In addition, we believe that, before suggesting a possible nonrandom association, it would be appropriate to exclude the possible known causes of hypospadias and to report clinical data about the external genitalia anatomy of the father and his male family members to exclude a rare hereditary case of this malformation. Third, we find that referring to a Yq microdeletion with the expression “gene mutation” is inaccurate and misleading. It is well known that each Yq microdeletion removes many genes, which play important roles in spermatogenesis. Thus, it would be more appropriate to refer to Yq microdeletions as “submicroscopic chromosomal rearrangements.” No reply required. Assisted reproductive technology may increase clinical mutation detection in male offspringFertility and SterilityVol. 90Issue 1PreviewTo investigate the risks of chromosome mutation after ART for couples with comparable genetic backgrounds. Full-Text PDF