Aberrations in pseudoautosomal regions (PARs) found in infertile men with Y-chromosome microdeletions

Abstract

Context: The pseudoautosomal regions (PARs) of the Y-chromosome undergo meiotic recombination with the X-chromosome. PAR mutations are associated with infertility and mental and stature disorders.

Objective: The aim of the study was to determine whether men with Y-chromosome microdeletions have structural defects in PARs.

Design and participants: Eighty-seven infertile men with Y-chromosome microdeletions and 35 controls were evaluated for chromosomal rearrangements using commercial or custom (X- and Y-chromosome) array comparative genomic hybridization or by quantitative PCR of selected PAR genes. Multisoftware-defined chromosomal gains or losses were validated by quantitative PCR and FISH.

Results: Array comparative genomic hybridization confirmed the AZF deletions identified by multiplex PCR. All men with Y-chromosome microdeletions and an abnormal karyotype displayed PAR abnormalities, as did 10% of men with Y-chromosome microdeletions and a normal karyotype. None of the control subjects or infertile men without Y-chromosome microdeletions had PAR duplications or deletions. SHOX aberrations occurred in 14 men (nine gains and five losses); four were short in stature (<10th percentile), and one was tall (>95th percentile). In contrast, the height of 23 men with Y-chromosome microdeletions and normal PARs was average at 176.8 cm (50th percentile).

Conclusions: Y-chromosome microdeletions can include PAR defects causing genomic disorders such as SHOX, which may be transmitted to offspring. Previously unrecognized PAR gains and losses in men with Y-chromosome microdeletions may have consequences for offspring.

Figures

Fig. 1.

SHOX duplication associated with abnormal stature in AZFbc infertile men. A, Demographics of four of the AZFbc patients with SHOX duplication. B, FISH analysis on subject 57658 [46,X,del(Y)(q11.2)] validated duplication on PAR1 and it localized on Yq. Probe RP11-1325A17 (includes SHOX) is shown in red, whereas control probe RP11-611P22 on the X chromosome is shown in green. C, View of aCGH of subject 61783 [46,X,idic(Yq11.2)] Y-chromosome showing a loss on Yq11.223-Yq11.23 that corresponds to the AZFbc region. Blue dots represent the relative hybridization to each probe in the aCGH.