Small Supernumerary Marker Chromosomes in Human Infertility

Abstract

Small supernumerary marker chromosomes (sSMC) are structurally abnormal chromosomes that cannot be unambiguously identified by banding cytogenetics. The objective of this study was to provide an overview of sSMC frequency and characterization in a context of infertility and to review the literature describing sSMC in relation with male and female infertility. Therefore, a systematic literature review on sSMC associated with infertility was conducted by means of a PubMed literature and a sSMC database (http://ssmc-tl.com/sSMC.html) search. A total of 234 patients with infertility were identified as carriers of sSMC. All chromosomes, except chromosomes 10, 19 and the X, were involved in sSMC, and in 72% the sSMC originated from acrocentric chromosomes. Euchromatic imbalances were caused by the presence of sSMC in 30% of the cases. Putative genes have been identified in only 1.2% of sSMC associated with infertility. The implication of sSMC in infertility could be due to a partial trisomy of some genes but also to mechanical effects perturbing meiosis. Further precise molecular and interphase-architecture studies on sSMC are needed in the future to characterize the relationship between this chromosomal anomaly and human infertility.

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

“…They may derive from all chromosomes, but sSMCs derived from gonosomes are often associated with Turner syndrome features and are excluded from this paper. Overall, adverse effects of sSMCs on fertility have been reported for male carriers [Mau-Holzmann, 2005;Liehr and Weise, 2007;Manvelyan et al, 2008;Liehr, 2014;Armanet et al, 2015], independent of the fact whether they were found in all studied peripheral blood cells or whether the sSMC was present only in a subset of the studied cells, i.e., in mosaic form [Liehr et al, 2013a].…”

“…There may be mutations in specific genes, like azoospermia factor ( AZF ) or cystic fibrosis transmembrane conductance regulator ( CFTR ) [Manvelyan et al, 2008;Wosnitzer et al, 2014;Röpke and Tüttelmann, 2017;Colaco and Modi, 2018;Vander Borght and Wyns, 2018]. Still, fertility may be impaired as well by (a) numerical chromosomal alterations, like (mosaic) trisomy or monosomy of (one of) the gonosomes [Mau-Holzmann, 2005;Manvelyan et al, 2007;Wosnitzer et al, 2014;Neto et al, 2016], (b) structural chromosomal abnormalities, like balanced rearrangements (translocations, insertions, inversions or even complex chromosomal rearrangements) [Liehr and Weise, 2007], or (c) a combination of numerical and structural chromosomal alterations, i.e., the presence of a small supernumerary marker chromosome (sSMC) [Manvelyan et al, 2008;Liehr, 2014;Armanet et al, 2015].…”

A Familial Small Supernumerary Marker Chromosome 15 Associated with Cryptic Mosaicism with Two Different Additional Marker Chromosomes Derived de novo from Chromosome 9: Detailed Case Study and Implications for Recurrent Pregnancy Loss

“…), usually without any visible clinical effects, their reproductive function may be affected due to the high probability of generating unbalanced gametes, either numerically or structurally, depending on the nature of the chromosomal abnormality. The heterochromatin excess present in the sSMCs of our patient could disturb correct chromosome pairing, and thus, this excess could influence the generation of unbalanced gametes [Ewers et al, 2010;Armanet et al, 2015]. At the same time, the formation of normal gametes should not be completely excluded, and the birth of a child with a normal karyotype is possible.…”

“…These marker chromosomes are associated with difficulties in conceiving and with repeated pregnancy loss, but the mechanism by which sSMCs influence fertility is not yet understood. It has been suggested that the negative effect of sSMCs on fertility could be due to partial trisomy of some genes related to reproduction, to mechanical effects perturbing meiosis, or to mosaicism level and possible uniparental disomies (UPD) of the chromosomes homologous to the sSMC [Starke et al, 2003;Armanet et al, 2015]. sSMCs are found 2.9 times more often in healthy persons with unexplained infertility than in the general population, and more than 50% of people with fertility problems inherited their marker chromosome from one of their parents, mostly from the mother's side.…”

Induced pluripotent stem cell generation from a man carrying a complex chromosomal rearrangement as a genetic model for infertility studies

“…Chromosomal abnormalities, including aneuploidies, deletions, microdeletions of the AZF region of the Y chromosome, duplications, small supernumerary marker chromosomes, translocations, insertions, and inversions, may be the underlying cause of the failure to complete meiosis45678910111213141516. Such chromosomal aberrations have been shown to affect meiotic synapsis and chromosome pairing17, resulting in both infertility and spontaneous abortions.…”