Sperm aneuploidy in fathers of Klinefelter's syndrome offspring assessed by multicolour fluorescent in situ hybridization using probes for chromosomes 6, 13, 18, 21, 22, X and Y.

BACKGROUND: It is still unclear if a recurrence risk would exist in fathers of an aneuploid offspring of paternal origin. We have studied disomy frequencies in spermatozoa from fathers having Klinefelter syndrome (KS) offspring or miscarriages. The effect of paternal age on sperm disomy percentages is also analysed. METHODS: Parental origin of 17 KS patients was carried out by amplification of X chromosome polymorphisms. Spermatozoa from their fathers were studied by multicolour fluorescent in situ hybridisation (FISH) using probes for chromosomes 6, 13, 18, 21, 22, X and Y. RESULTS: In 53% of KS cases studied the additional X chromosome was of paternal origin. The paternally transmitted KS group of fathers showed significantly higher frequencies for XY disomy sperm as compared to fathers of the maternal-origin group. A correlation between paternal age and XY disomy frequencies was only found in the paternally derived cases. In contrast, similar disomy frequencies for all autosomes analysed were found in both groups of fathers. CONCLUSIONS: XY disomy frequencies increase with advancing paternal age only in fathers with paternally inherited KS offspring.

Male-to-male transmission of X-linked Alport syndrome in a boy with a 47,XXY karyotype.

Alport syndrome (AS) is a genetically heterogeneous renal hereditary disease. Male-to-male transmission has been considered fully indicative of autosomal dominant AS. We report a family with male-to-male transmission of X-linked AS due to an extra X chromosome of paternal origin in the proband. Linkage analysis excluded the autosomal loci and demonstrated segregation with the COL4A5 locus (Xq22.3). Sperm FISH analysis from his father detected an increased XY disomy. Mutation screening of the COL4A5 gene identified a splicing mutation, c.4688G>A. The proband and his paternal grandmother showed random X chromosome inactivation. However, a preferential expression of the aberrantly spliced transcript was detected in the proband when compared to his grandmother. This finding could explain why the AS phenotype of this 47,XXY boy resembles more an affected male than a female carrier. This is the first reported case of concurrence of Alport and Klinefelter syndromes.

Mitotic and meiotic behaviour of a naturally transmitted ring Y chromosome: reproductive risk evaluation.

BACKGROUND: The mitotic and meiotic behaviour of a transmitted ring Y [r(Y)] chromosome from a father to his Klinefelter syndrome (KS) son, and the mechanism of ring formation are analysed herein. To our knowledge, this is the first reported case of natural transmission of an r(Y). METHODS AND RESULTS: Amplification of X chromosome polymorphisms by PCR showed that the KS was of paternal origin. G-banding and fluorescence in situ hybridization (FISH) studies revealed a similar percentage of mosaicism in father and son by mitotic loss of r(Y). SRY gene and Y marker amplification by PCR, FISH with subtelomeric probes for Xp/Yp and Xq/Yq, and comparative genomic hybridization (CGH) analyses indicated the intactness of the Y chromosome from SRY to subtelomere Yq. FISH analysis of sperm from the father showed significantly higher frequencies (P<0.005) for diploidy and for 6, 13, 18, 21, 22, XX, XY disomies than those observed in control donors. CONCLUSIONS: An r(Y) with low material loss can be naturally transmitted, showing similar mitotic behaviour in the offspring. The presence of an r(Y) chromosome in germinal cells increased the risk of fathering offspring with numerical abnormalities, even for chromosomes not involved in the arrangement.