Impaired Spermatogenesis due to Small Supernumerary Marker Chromosomes: The Reason for Infertility Is Only Reliably Ascertainable by Cytogenetics

Abstract

Infertile male with small supernumerary marker chromosomes (sSMCs) were studied. Overall, 37 own patients and 166 cases from the literature were included. sSMCs of our own cases were characterized by multicolor-FISH probe sets. Available clinical data of the infertile males were also evaluated, and meta-analysis on suitability of molecular karyotyping for sSMC characterization was done. As a result, sSMCs can be optimally characterized by single-cell directed (molecular) cytogenetics. In infertile males, sSMCs derive predominantly from one of the acrocentric chromosomes, mainly chromosomes 15, 14, and 22. Interestingly, altered spermiograms were found in 62% of the males with an sSMC, while the remainder cases had infertility in connection with recurrent spontaneous abortions. Meta-analysis for detectability of sSMCs by aCGH revealed that 81-87% of the cases would have not been picked up by exclusive use of that approach. Thus, as impaired spermatogenesis is known to be indicative for gross chromosomal anomalies in infertile male patients, it can be concluded from this study that the presence of sSMCs also needs to be considered. However, sSMCs can only be reliably detected by standard karyotyping and not by modern high throughput approaches like aCGH and next-generation sequencing.

Molecular cytogenetic characterization of small supernumerary marker 15 in infertile male: A case report

“…of sSMCs and detection of genomic copy number variations, chromosomal breakpoints and the genes involved (4,14). In the present study, CMA analysis detected a 0.44-Mb interstitial duplication in 6q25.3q26, which led to arr[hg19]6q2 5.3q26(160,569,492-161,010,647)x3.…”

“…Of note, sSMCs may lead to only fertility problems without the appearance of any additional clinical symptoms (1). Liehr and Hamid Al-Rikabi (4) pointed out that most sSMCs in infertile males were derived from acrocentric chromosomes, particularly sSMC (15), which accounted for up to 40% of all sSMCs. Patients with sSMC (15) are generally clinically normal, while the risk of oligo-or azoospermia is increased in infertile males, which may affect spermatogenesis (24,25).…”

“…Male infertility, occurs in a clinically population and is influenced by factors including hormone status, age, exercise, obesity, infectious disease and immunological or psychological factors. In addition, various genetic impairments are associated with problems of fertility, including azoospermia factor deletion, mutations in the cystic fibrosis transmembrane conductance regulator and numerical/structural chromosomal abnormalities (3,4).…”

Ring Chromosome 20 Syndrome: Genetics, Clinical Characteristics, and Overlapping Phenotypes

“…Difficult-to-treat frontal lobe epilepsy with typical EEG pattern, ID manifesting after seizure onset in an otherwise normally developing child or adolescent with no facial dysmorphisms or birth defects, and behavioral changes are the core clinical manifestations that should lead the neurologist and/or the clinical geneticist to suspect r(20) syndrome ( Table 4). We advocate for offering karyotype with 50-100 metaphases count in such cases before requesting other molecular analyses such as CMA and Next Generation Sequencing approaches (i.e., panels, WES or WGS) and whenever these analyses return negative results in patients with overlapping phenotypes of r (20) syndrome (1,95). Conventional karyotype is a cost-effective and fast test that should not be neglected in the diagnostic approach of patients with these characteristics.…”

Chromosomes in the DNA era: Perspectives in diagnostics and research

“…GTG G-bands by trypsin using Giemsa, FISH fluorescence in situ hybridization, CMA chromosomal microarray, NGS next-generation sequencing, CNV copy number variation, DS Down Syndrome, UPD uniparental disomy, LOH loss of heterozygosity, EBM Einheitlicher Bewertungsmaßstab autism, epilepsy, dysmorphic features, developmental delay, and congenital malformations, or a combination of the aforementioned characteristics. However, up to~80% of infertile patients with a small supernumerary marker chromosome would be missed in CMA [18].…”