Clinical relevance of Y-linked CNV screening in male infertility: new insights based on the 8-year experience of a diagnostic genetic laboratory

Abstract

AZF microdeletion screening is routinely performed in the diagnostic work-up for male infertility; however, some issues remain debated. In this study, we provide insights into the sperm concentration cutoff value for routine testing, the predictive value of AZFc deletion for testicular sperm retrieval and the Y-background contribution to the interpopulation variability of deletion frequencies. In the Spanish population, partial AZFc rearrangements have been poorly explored and no data exist on partial duplications. In our study, 27/806 (3.3%) patients carried complete AZF deletions. All were azoo/cryptozoospermic, except for one whose sperm concentration was 2 Â 10 6 /ml. In AZFc-deleted men, we observed a lower sperm recovery rate upon conventional TESE (9.1%) compared with the literature (60-80% with microTESE). Haplogroup E was the most represented among non-Spanish and hgr P among Spanish AZF deletion carriers. The analysis of AZFc partial rearrangements included 330 idiopathic infertile patients and 385 controls of Spanish origin. Gr/gr deletion, but not AZFc partial duplications, was significantly associated with spermatogenic impairment. Our data integrated with the literature suggest that: (1) routine AZF microdeletion testing could eventually include only men with r2 Â 10 6 /ml; (2) classical TESE is associated with low sperm recovery rate in azoospermic AZFc-deleted men, and therefore microTESE should be preferred; (3) Y background could partially explain the differences in deletion frequencies among populations. Finally, our data on gr/gr deletion further support the inclusion of this genetic test in the work-up of infertile men, whereas partial AZFc duplications do not represent a risk for spermatogenic failure in the Spanish population.

Genetics of male infertility: from research to clinic

“…Ye et al (2013) found a significantly higher frequency of partial duplications in the infertile patients (4.0%) compared to controls (0.7%) in the Chinese-Yi population. Contrastingly, in the analysis by Lo Giacco et al (2014a), performed on a study population including prevalently Spanish subjects, AZFc duplications were found at comparable frequencies in patients (4.9%) and controls (3.5%). Seemingly, this discordance reflects mere ethnic differences; therefore, if increased AZFc gene content does play a role in spermatogenic impairment, the effect is probably modulated by population-specific factors.…”

Susceptibility of gr/gr rearrangements to azoospermia or oligozoospermia is dependent on DAZ and CDY1 gene copy deletions

“…Amongst the various possible rearrangements that can occur, three major types of AZFc subdeletions viz. gr/gr, b1/b3 and b2/b3 have been consistently identified [11][12][13]. The gr/gr deletions (which is most frequently observed) remove almost half the gene content of AZFc involving two of the four copies of the DAZ (deleted in azoospermia) gene, one of the two copies of CDY1 (chromodomain protein on Y, 1) and BPY2 (basic protein Y-2) genes; the b1/b3 and b2/b3 deletions also remove the similar amount of genetic material and the same genes [14].…”

“…While in some studies the frequency of AZFc subdeletions (mainly the gr/gr) is higher in infertile men as compared to fertile controls [5,11,[20][21][22]; others have failed to confirm this association [23,24]. Based on four meta-analysis studies and a large population study involving >20,000 individuals it appears that the gr/gr deletion is a risk factor for male infertility [13,20,21,25,26]; the odds ratio is estimated to be 1.4-2.4 [5,20,21,25,26].…”

“…It has been observed that the Europeans and the Han Chinese have a strong association of gr/gr deletions with male infertility [11,22,27]; the American and African men with gr/gr deletions do not seem to be susceptible to azoospermia or oligozoospermia [20,21,[28][29][30]. In the Asian population, the gr/gr deletions are not associated with male infertility in the Malaysian and Japanese men; a significant association has been observed in the Korean and Chinese men [20,21,27,[31][32][33].…”

New Molecular Technologies in Genetic Diagnosis of Male Infertility

“…Исследование вариаций числа копий при нарушении репродуктивной функции В последние годы начато активное исследование микроструктурных перестроек хромосом, CNV, в том числе при различных формах нарушения развития и функции органов мужской и женской репродуктивной системы, при бесплодии и невынашивании беременно-сти, а также для детекции (скрининга) хромосомных му-таций у эмбриона до его имплантации и у плодов при потере беременности [16][17][18][19][20][21][22][23][24][25][26][27][28].…”