Development of a high-resolution Y-chromosome microarray for improved male infertility diagnosis

Objective To develop a novel clinical test using microarray technology as a high-resolution alternative to current methods for detection of known and novel microdeletions on the Y chromosome. Design Custom Agilent 8x15K array comparative genomic hybridization (aCGH) with 10,162 probes on an average probe spacing of 2.5 kb across the euchromatic region of the Y chromosome. Setting Clinical diagnostic laboratory. Patient(s) Men with infertility (n = 104) and controls with proven fertility (n = 148). Intervention(s) Microarray genotyping of DNA. Main Outcome Measure(s) Gene copy number variation determined by log ratio of probe signal intensity against a DNA reference. Result(s) Our aCGH experiments found all known AZF microdeletions as well as additional unbalanced structural alterations. In addition to complete AZF microdeletions, we found that AZFc partial deletions represent a risk factor for male infertility. In total, aCGH-based detection achieved a diagnostic yield of ∼11% and also revealed additional potentially etiologic copy number variations requiring further characterization. Conclusion(s) The aCGH approach is a reliable high-resolution alternative to multiplex polymerase chain reaction for the discovery of pathogenic chromosome Y microdeletions in male infertility.