Complex Chromosomal Rearrangement Causes Male Azoospermia: A Case Report and Literature Review

Abstract

Background: Male carriers of complex chromosomal rearrangements (CCRs) may have decreased fertility and usually present with azoospermia, oligospermia or teratospermia.Methods: High-resolution karyotype analysis using G-banding on peripheral blood lymphocytes was performed in an azoospermic male. Copy number variations (CNVs) were detected by chromosomal microarray analysis, and genetic variations were determined by long-read nanopore sequencing with Sanger sequencing for breakpoint confirmation.Results: The karyotype of the patient was 46,XY,t(4;21)(p11;p11),t(5;6;14)(p13q22;p22q22;q22), which did not involve CNVs with clinical significance. Twelve breakpoints in chromosomes 5, 6, and 14 were found by long-read nanopore sequencing. Reports on 17 males carrying CCRs with azoospermia were also reviewed.Conclusion: The extent of asynaptic regions in synaptonemal complexes during pachytene and the disruption of genes involved in male gametogenesis may cause azoospermia in CCR carriers.

Familial transmission of chromoanagenesis leads to unpredictable unbalanced rearrangements through meiotic recombination

“…Interestingly, we observed a high proportion of chromoanagenesis transmitted from fathers, 3/6 in our study and 3/12 reported before 13,17,18 . It is known that men who are carriers of complex rearrangement are mostly infertile or subfertile due to deficiency or arrest of spermatogenesis 9,25 . Indeed, the meiosis I prophase checkpoint is supposed to be less permissive in men than in women, and spermatogenesis is consequently strongly disturbed by complex changes 11,26,27 …”

“…As a consequence, CCRs in men are associated with a reduced proportion of normal and balanced gametes and defects in spermatogenesis. 1,9 It has also been observed that chiasmata numbers are reduced in complex rearrangements, leading to less frequent recombination events. 10,11 Nevertheless, stable and unstable transmissions of chromoanagenesis have been reported.…”

“…A high number of breakpoints may give rise to complex figures to achieve this pairing step 8 and the risk of having abnormal gametes increases with the complexity of the rearrangements. As a consequence, CCRs in men are associated with a reduced proportion of normal and balanced gametes and defects in spermatogenesis 1,9 . It has also been observed that chiasmata numbers are reduced in complex rearrangements, leading to less frequent recombination events 10,11 .…”

Identification of complex and cryptic chromosomal rearrangements by optical genome mapping

“…The unbalanced genomic changes were expected to contribute to adverse pregnancy outcomes for the fetus and pregnancy. Carriers of cryptic balanced chromosomal translocations are prone to adverse reproductive events, such as infertility, recurrent abortion, suspended embryo development, stillbirth, teratogenesis and birth defects [ 30 – 32 ]. Thus, this kind of aberration, which is characterized by occult findings during routine cytogenetic analyses and serious clinical consequences, needs to be taken seriously.…”

ARecql5mutant enables complex chromosomal engineering of mouse zygotes

“…Asymmetric disjunction results in a wide range of highly imbalanced gametes, many of which do not survive until the end of spermatogenesis 17 . Breakpoints in intergenic regions may disturb the interactions between the promoter and transcriptional units with its cis-acting regulators through positional effects, thus severely affecting gene expression 18 .…”