Sperm rates of 7q11.23, 15q11q13 and 22q11.2 deletions and duplications: a FISH approach

Abstract

Genomic disorders are human diseases caused by meiotic chromosomal rearrangements of unstable regions flanked by Low Copy Repeats (LCRs). LCRs act as substrates for Non-Allelic Homologous Recombination (NAHR) leading to deletions and duplications. The aim of this study was to assess the basal frequency of deletions and duplications of the 7q11.23, 15q11-q13 and 22q11.2 regions in spermatozoa from control donors to check differences in the susceptibility to generate anomalies and to assess the contribution of intra- and inter-chromatid NAHR events. Semen samples from ten control donors were processed by FISH. A customized combination of probes was used to discriminate among normal, deleted and duplicated sperm genotypes. A minimum of 10,000 sperm were assessed per sample and region. There were no differences in the mean frequency of deletions and duplications (del + dup) among the 7q11.23, 15q11-q13 and 22q11.2 regions (frequency ± SEM, 0.37 ± 0.02; 0.46 ± 0.07 and 0.27 ± 0.07%, respectively) (P = 0.122). Nevertheless, hierarchical cluster analysis reveals interindividual differences suggesting that particular haplotypes could be the main source of variability in NAHR rates. The mean frequency of deletions was not different from the mean frequency of duplications in the 7q11.23 (P = 0.202) and 15q11-q13 (P = 0.609) regions, indicating a predominant inter-chromatid NAHR. By contrast, in the 22q11.2 region the frequency of deletions slightly exceed duplications (P = 0.032), although at the individual level any donor showed differences. Altogether, our results support the inter-chromatid NAHR as the predominant mechanism involved in the generation of sperm deletions and duplications.

Screening of copy number variants in the 22q11.2 region of congenital heart disease patients from the São Miguel Island, Azores, revealed the second patient with a triplication

“…The 22q11.2 deletion syndrome has been reported as the most common deletion syndrome [4,9]. With the use of MLPA, molecular cytogenetic and cytogenomic methods, we observed that two unrelated patients (A and D) had this syndrome, both carrying a 2.5 Mb deletion of the 22q11.2 region.…”

“…These structural variants are strongly associated with genetic syndromes [1]. The most common example is the 22q11.2 deletion syndrome, which is estimated to affect approximately 1 in 4000 live births [4] and results most commonly from a 3 Mb deletion in the 22q11.2 region [4-7]. This region contains approximately 40 genes [8], being the TBX1 and COMT the most relevant [9].…”

“…This region contains approximately 40 genes [8], being the TBX1 and COMT the most relevant [9]. Genomic rearrangements in the 22q11.2 region are due to the presence of several copies of low-copy repeat sequences (LCR22) that mediate inter-chromosomal (inter-chromatid) non-allelic homologous recombination (NAHR) [4,7,10]. …”

Co-occurrence of recurrent duplications of the DiGeorge syndrome region on both chromosome 22 homologues due to inherited and de novo events

“…In this work, we clearly demonstrate that the proband in family 1 had homozygous duplications in the typical DGS region with one duplication inherited, and the other a de novo event during spermatogenesis. A study suggested that interchromatid NAHR is the predominant mechanism involved in the generation of sperm deletions and duplications 27. Consistently, this de novo duplication was most likely generated through a paternal interchromosomal NAHR between LCRs.…”

Reciprocal 22q11.2 Deletion and Duplication in Siblings with Karyotypically Normal Parents

“…The reciprocal duplication is observed at a lower frequency. By sperm typing, Molina et al [2011] determined genotypic frequencies of 0.17 ± 0.2% for the deletion and 0.12 ± 0.03% for the duplication. The difference can be explained by the causal mechanisms of the deletion and duplication.…”