A Novel Chromosomal Translocation Identified due to Complex Genetic Instability in iPSC Generated for Choroideremia

• Published in: Cells (Basel, Switzerland) Vol. 8; no. 9; p. 1068
• Main Authors: Erkilic, Nejla, Gatinois, Vincent, Torriano, Simona, Bouret, Pauline, Sanjurjo-Soriano, Carla, Luca, Valerie De, Damodar, Krishna, Cereso, Nicolas, Puechberty, Jacques, Sanchez-Alcudia, Rocio, Hamel, Christian P, Ayuso, Carmen, Meunier, Isabelle, Pellestor, Franck, Kalatzis, Vasiliki
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 11.09.2019; MDPI
• Subjects: Amino acids; Biomedical research; Blood cells; Cell culture; Cell Differentiation - genetics; Cells, Cultured; Cellular Biology; Cellular Reprogramming - genetics; choroideremia; Choroideremia - genetics; Chromosome aberrations; Chromosome translocations; Chromosomes; Chromosomes, Human, Pair 12 - genetics; Chromosomes, Human, Pair 20 - genetics; Chromosomes, Human, Pair 5 - genetics; Cloning; Congenital defects; Disease; Fibroblasts; Genetic counseling; genetic instability; Genetics; Genomic instability; Human health and pathology; Humans; induced pluripotent stem cells; Induced Pluripotent Stem Cells - pathology; inherited retinal dystrophies; Karyotype; Karyotypes; Life Sciences; Photoreceptors; Pluripotency; Reproductive failure; Retina; Retinal degeneration; retinal differentiation; Retinal Dystrophies - genetics; Siblings; Somatic cells; Stem cells; Translocation, Genetic - genetics; underprenylated cell phenotype; Italy; France; Japan; Germany; genetic instability; induced pluripotent stem cells; inherited retinal dystrophies; choroideremia; retinal differentiation; underprenylated cell phenotype
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells8091068

Induced pluripotent stem cells (iPSCs) have revolutionized the study of human diseases as they can renew indefinitely, undergo multi-lineage differentiation, and generate disease-specific models. However, the difficulty of working with iPSCs is that they are prone to genetic instability. Furthermore, genetically unstable iPSCs are often discarded, as they can have unforeseen consequences on pathophysiological or therapeutic read-outs. We generated iPSCs from two brothers of a previously unstudied family affected with the inherited retinal dystrophy choroideremia. We detected complex rearrangements involving chromosomes 12, 20 and/or 5 in the generated iPSCs. Suspecting an underlying chromosomal aberration, we performed karyotype analysis of the original fibroblasts, and of blood cells from additional family members. We identified a novel chromosomal translocation t(12;20)(q24.3;q11.2) segregating in this family. We determined that the translocation was balanced and did not impact subsequent retinal differentiation. We show for the first time that an undetected genetic instability in somatic cells can breed further instability upon reprogramming. Therefore, the detection of chromosomal aberrations in iPSCs should not be disregarded, as they may reveal rearrangements segregating in families. Furthermore, as such rearrangements are often associated with reproductive failure or birth defects, this in turn has important consequences for genetic counseling of family members.