A germline chimeric KANK1-DMRT1 transcript derived from a complex structural variant is associated with a congenital heart defect segregating across five generations

• Published in: Chromosome research 2024-03, Vol.32 (2), p.6, Article 6
• Main Authors: da Costa, Silvia Souza, Fishman, Veniamin, Pinheiro, Mara, Rodrigueiro, Andre, Sanseverino, Maria Teresa, Zielinsky, Paulo, Carvalho, Claudia M. B., Rosenberg, Carla, Krepischi, Ana Cristina Victorino
• Format: Article
• Language: English
• Subjects: Animal Genetics and Genomics; Aorta; Biomedical and Life Sciences; Breakpoints; Cell Biology; Chromosome 9; Gene mapping; Genomes; Genomic analysis; Genotypes; Heart; Human Genetics; Karyotypes; Life Sciences; Molecular modelling; Phenotypes; Plant Genetics and Genomics; Pulmonary arteries; Pulmonary artery; Stenosis
• ISSN: 1573-6849; 0967-3849; 1573-6849
• DOI: 10.1007/s10577-024-09750-2

Structural variants (SVs) pose a challenge to detect and interpret, but their study provides novel biological insights and molecular diagnosis underlying rare diseases. The aim of this study was to resolve a 9p24 rearrangement segregating in a family through five generations with a congenital heart defect (congenital pulmonary and aortic valvular stenosis and pulmonary artery stenosis), by applying a combined genomic analysis. The analysis involved multiple techniques, including karyotype, chromosomal microarray analysis (CMA), FISH, genome sequencing (GS), RNA-seq, and optical genome mapping (OGM). A complex 9p24 SV was hinted at by CMA results, showing three interspersed duplicated segments. Combined GS and OGM analyses revealed that the 9p24 duplications constitute a complex SV, on which a set of breakpoints matches the boundaries of the CMA duplicated sequences. The proposed structure for this complex rearrangement implies three duplications associated with an inversion of ~ 2 Mb region on chromosome 9 and a SINE element insertion at the more distal breakpoint. Interestingly, this genomic structure of rearrangement forms a chimeric transcript of the KANK1/DMRT1 loci , which was confirmed by both RNA-seq and Sanger sequencing on blood samples from 9p24 rearrangement carriers. Altogether with breakpoint amplification and FISH analysis, this combined approach allowed a deep characterization of this complex rearrangement. Although the genotype–phenotype correlation remains elusive from the molecular mechanism point of view, this study identified a large genomic rearrangement at 9p24 segregating with a familial congenital heart defect, revealing a genetic biomarker that was successfully applied for embryo selection, changing the reproductive perspective of affected individuals.