Recurrent X chromosome-linked deletions: discovery of new genetic factors in male infertility

Abstract

We provide the first evidence for X chromosome-linked recurrent deletions associated with spermatogenic impairment. CNV67, specific to spermatogenic anomaly and with a frequency of 1.1% in oligo/azoospermic men, resembles the AZF regions on the Y chromosome with potential clinical implications.

Genetics of male infertility: from research to clinic

“…The first study analyzed three recurrent deletions (frequency O1%) in a large case-control setting (nZ1255) for their exclusive (CNV67) and prevalent (CNV64 and CNV69) presence in patients. For instance, deletion carriers displayed a higher probability of having impaired spermatogenesis (ORZ1.9 and 2.2 for CNV64 and CNV69 respectively) as well as sperm concentration and total motile sperm number was lower in carriers compared to non-carriers The most interesting deletion was CNV67 because it was exclusively found in patients with a frequency of 1.1% (P!0.01) and is likely to involve the MAGE9A genea CTA family member -and/or its regulatory elements (Lo Giacco et al 2014b). Similarly, a follow-up study was performed on five selected gains (DUP1A, DUP5, DUP20, DUP26 and DUP40), which include, or are in close proximity to, genes with testis-specific expression and potential implication in spermatogenesis (Chianese et al 2014).…”

“…In fact, the two variants DUP1a and CNV69 were objects of large follow-up studies, together with other recurrent deletions, CNV67 and CNV64 (Chianese et al 2014, Lo Giacco et al 2014b. The first study analyzed three recurrent deletions (frequency O1%) in a large case-control setting (nZ1255) for their exclusive (CNV67) and prevalent (CNV64 and CNV69) presence in patients.…”

Clinical and molecular characterization of Y microdeletions and X‐linked CNV67 implications in male fertility: a 20‐year experience

“…In 2017, our group found a 2% prevalence of CNV67 deletion in a sample of 100 Portuguese idiopathic infertile men, with different sperm counts (Costa et al ., ), selected from our 4000 cases database. The percentage found in this Portuguese population was significantly higher than the 1.1% percentage reported by larger surveys in other populations (Krausz et al ., ; Lo Giacco et al ., ). Our initial aim was to duplicate the number of infertile patients screened for CNV67 to obtain a wider sample and corroborate the findings of Costa et al .…”

“…After screening 400 cases, we found a CNV67 deletion frequency of 1.2% (5/400) in the studied sample. Even though our sample size was still small, we found a prevalence of this deletion in our population similar to the previously reported by other authors (Krausz et al ., ; Lo Giacco et al ., ). This finding supports the CNV67 deletion percentage found in the international studies and draws our Portuguese population nearer the others, which hypothesizes that the higher frequency found in the first study (Costa et al ., ) was because of the small sample size.…”

“…CNV67 was exclusively deleted in patients with spermatogenic impairment in our and in the previous studies, showing a consistent genotype–phenotype correlation and a significant prevalence (Krausz et al ., ; Lo Giacco et al ., ; Costa et al ., ). Furthermore, this deletion may remove MAGEA9B (melanoma antigen family A, 9B) gene, belonging to the cancer testis Antigen (CTA) X‐linked family specifically expressed on the male gonads and some tumours (Shen et al ., ), and affects X chromosome reading frame (CXorf40A) and regulatory elements of heat shock transcription factor family, X‐linked 1/2 ( HSFX1/2 ) (Krausz et al ., ; Lo Giacco et al ., ).…”