Copy number variation associated with meiotic arrest in idiopathic male infertility.

OBJECTIVE:To assess the association between copy number variations (CNVs) and meiotic arrest and azoospermic men. DESIGN:Genetic association study. SETTING:University. PATIENT(S):Australian men: 19 with histologically confirmed meiotic arrest, 110 men with azoospermia in the absence of histologic data, and 97 fertile men (controls). INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):The identification of CNV by microarray and/or multiplex ligation-dependent probe amplification (MLPA), and the localization of unique CNV encoded proteins to the human testis. RESULT(S):Microarray identified two CNVs unique to meiosis arrest patients. One containing the MYRIP gene and a second containing LRRC4C and the long noncoding RNA LOC100507205. All three genes are transcribed in the human testis, and MYRIP and LRRC4C localize to meiotic cells. The reverse genetic screen for CNVs in meiosis genes identified in mouse models further identified CNVs including HSPA2 as being associated with azoospermia. CONCLUSION(S):These data raise the possibility that, while relatively rare, CNVs may contribute to human male infertility and that CNV screening should be incorporated into long-term plans for genome profiling as a diagnostic tool.