Frequency of XY Sperm Increases with Age in Fathers of Boys with Klinefelter Syndrome

Abstract

With increasing availability of drugs for impotence and advanced reproductive technologies for the treatment of subfertility, more men are fathering children at advanced ages. We conducted a study of the chromosomal content of sperm of healthy men aged 24-57 years to (a) determine whether father's age was associated with increasing frequencies of aneuploid sperm including XY, disomy X, disomy Y, disomy 21, and sperm diploidy, and (b) examine the association between the frequencies of disomy 21 and sex-chromosomal aneuploidies. The study group consisted of 38 fathers of boys with Klinefelter syndrome (47, XXY) recruited nationwide, and sperm aneuploidy was assessed using multicolor X-Y-21 sperm FISH ( approximately 10,000 sperm per donor). Paternal age was significantly correlated with the sex ratio of sperm (Y/X; P=.006) and with the frequency of XY sperm (P=.02), with a clear trend with age by decades (P<.006). Compared with fathers in their 20s (who had an average frequency of 7.5 XY sperm per 10,000), the frequencies of XY sperm were 10% higher among fathers in their 30s, 31% higher among those in their 40s, and 160% higher among those in their 50s (95% CI 69%-300%). However, there was no evidence for age effects on frequencies of sperm carrying nullisomy sex; disomies X, Y, or 21; or meiosis I or II diploidies. The frequencies of disomy 21 sperm were significantly associated with sex-chromosomal aneuploidy (P=.04)-in particular, with disomy X (P=.004), but disomy 21 sperm did not preferentially carry either sex chromosome. These findings suggest that older fathers produce higher frequencies of XY sperm, which may place them at higher risk of fathering boys with Klinefelter syndrome, and that age effects on sperm aneuploidy are chromosome specific.

The effects of male aging on semen quality, sperm DNA fragmentation and chromosomal abnormalities in an infertile population

“…Using a triple color FISH X-Y-8, we did not find a paternal age effect on sex chromosomes disomy (XX, YY, XY) in infertile patients and in donors. Our results are in accordance with the data of Bosch et al [39,40] and Luetjens et al [16], but in discordance with others studies which found an effect of age on the production of disomic sex chromosomes with varying results for XX, YY, XY [41][42][43][44][45][46][47].…”

The effects of advanced paternal age on fertility

“…69 With regard to Klinefelter syndrome, the population risk is around 1 in 500, 72 and one study found this to be increased to 1 in 312 in men of APA .50 years old. 73 Other work has suggested that there is no significant relationship of APA with either the paternal or maternal age in Klinefelter syndrome. 1,74 An association between increased rates of cancer in children of fathers with APA has been suggested.…”

Scoring of sperm chromosomal abnormalities by manual and automated approaches: qualitative and quantitative comparisons

“…It has been well documented that severe male infer tility correlates with a significant increase in sperm aneuploidy; in addition, other factors such as paternal age, chemotherapy treatment, smoking and alcohol have also been associated with increased sperm aneuploidy [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Given the significant increased risk of sperm aneuploidy in infertile men, concerns have been raised regarding whether these individuals are at a higher risk of giving rise to aneuploid pregnancies when treated by intracytoplasmic sperm injection (ICSI) [17].…”