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Novel pericentric inversion inv(9)(p23q22.3) in unrelated individuals with fertility problems in the Southeast European population


Pericentric inversions are among the known polymorphisms detected in the general population at a frequency of 1–2%. Despite their generally benign nature, pericentric inversions affect the reproductive potential of carriers by increasing the risk for unbalanced live-born offspring, miscarriages, or other fertility problems. Here we present a novel large pericentric inversion of chromosome 9, inv(9)(p23q22.3), detected in 30 heterozygote carriers, 24 from seven apparently unrelated families and 6 isolated patients, where the probands were mainly referred for fertility and prenatal problems. The inversion carries a significant risk for recombinant abnormal chromosomes, as in two families one supernumerary rec(9)dup(9p) and one rec(9)dup(9q) were identified, leading to neonatal death and miscarriage, respectively. The inversion carriers were identified by three different laboratories in Greece, Cyprus and Germany respectively, however all carriers have Southeast European origin. The inversion appears to be more frequent in the Greek population, as the majority of the carriers were identified in Greece. We were able to determine that the inversion is identical in all individuals included in the study by applying a combination of several methodologies, such as karyotype, fluorescence in situ hybridization (FISH), chromosomal microarrays (CMA) and haplotype analysis. In addition, haplotype analysis supports that the present inversion is identical by descent (IBD) inherited from a single common ancestor. Our results are, therefore, highly indicative of a founder effect of this inversion, presumably reflecting an event that was present in a small number of individuals that migrated to the current Southeast Europe/Northern Greece from a larger population.

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Fig. 1: The geographical distribution of origin of the heterozygote inv(9)(p24q22.3) carrier patients in Southeast Europe.
Fig. 2: Cytogenetic results.
Fig. 3: FISH results.
Fig. 4: Results of SNP-microarray analysis. Affymetrix Cytoscan™ HD Suite with 2.4 million copy number markers and 750.000 SNP markers was used.
Fig. 5: Graphical representation of the repetitive elements.

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VV conceived and designed the project. VV and CS prepared the manuscript. CS and SMR contributed equally in the design and execution of the experiments. SMR contributed in the final preparation of the manuscript. SF contributed in the final corrections of the manuscript.

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Correspondence to Voula Velissariou.

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This study was approved by the scientific committee of Bioiatriki Healthcare Group and all participants provided written informed consent prior to testing and participation.

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Sismani, C., Rapti, SM., Iliopoulou, P. et al. Novel pericentric inversion inv(9)(p23q22.3) in unrelated individuals with fertility problems in the Southeast European population. J Hum Genet 65, 783–795 (2020).

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