Abstract Wolf–Hirschhorn syndrome (WHS) is a devastating congenital disease caused by deletions on the short arm of chromosome 4 (4p), for which no curative treatments currently exist. To facilitate the development of therapeutic strategies, the development of experimental models of WHS is crucial for investigating its etiology and pathogenesis, which remain elusive. In this study, we successfully generated human induced pluripotent stem cells (hiPSCs) from three fibroblast lines from WHS patients. We then characterized these hiPSCs, along with one hiPSC line previously generated from peripheral blood mononuclear cells, as part of a Japanese nationwide project. All four hiPSC lines exhibited characteristics of self-renewal, pluripotency, and karyotypes with expected 4p deletions. Copy number variation microarray analysis revealed that these WHS-specific hiPSCs carried hemizygous deletions in p15.1–p16.3 regions, commonly encompassing 100 genes. Transcriptome analysis showed that the expression of these genes faithfully reflected hemizygous deletion in these WHS-specific hiPSCs and that these down-regulated genes were associated with the development of neural crest cells. These results indicate that WHS-specific hiPSCs can recapitulate the abnormal genomic structure genes related to and the gene expression profile observed in WHS patients. Given the limited understanding of the molecular pathogenesis of WHS, these cellular resources will be instrumental in modeling disease phenotypes and in advancing novel therapies for this syndrome.
Shimizu et al. (Fri,) studied this question.