ABSTRACT Complex chromosomal rearrangements (CCRs) are structural variants involving multiple breakpoints. Among these, intrachromosomal balanced CCRs containing inversions pose significant diagnostic and interpretative challenges, as conventional cytogenetic methods including G‐banded karyotype, FISH, and chromosomal microarray lack the resolution needed to determine their structural complexity. Paracentric inversions are traditionally associated with a negligible risk of a viable unbalanced offspring. Here, we describe a familial intrachromosomal rearrangement comprising a complex paracentric inversion of chromosome 6q, transmitted across multiple generations, that resulted in five affected children with recombinant chromosomes harboring reciprocal interstitial gains and losses on 6q. High‐resolution optical genome mapping revealed a ~75 Mb parental balanced CCR, formed by multiple sequential paracentric inversions that contain a single ~13 Mb correctly oriented segment. Bias meiotic recombination between homologous chromosomes 6 within this segment is responsible for recurrent unbalanced products resembling recombinant chromosomes typically associated with pericentric inversions. These findings challenge the prevailing assumption that paracentric inversions rarely result in viable recombinant chromosomes and demonstrate how complex chromosomal architecture can directly influence meiotic behavior and reproductive outcomes. Our study underscores the importance of high‐resolution genomic technologies for accurate diagnosis, interpretation of a molecular mechanism, and reproductive risk assessment in carriers of CCR.
Babcock et al. (2026) studied this question.