Clinical characteristics and induced pluripotent stem cells (iPSCs) disease model of Harel-Yoon syndrome caused by compound heterozygous ATAD3A variants.

ATPase family AAA-domain-containing protein 3 A (ATAD3A) is enriched on the mitochondrial membrane and is essential to the maintenance of mitochondrial structure and function. Variants of the ATAD3A gene can lead to Harel-Yoon syndrome (HAYOS), a developmental defect in neurological, cardiovascular, and other systems. This study aims to develop induced pluripotent stem cells (iPSCs) from the somatic cells of a patient (ZJUCHYLi001-A) and a negative control (ZJUCHYLi002-A) as effective tools for further investigations into the etiology of ATAD3A variant-related disease. We described and analyzed the clinical manifestations of the proband and her family members. Somatic cells from the proband and a negative control were collected and reprogrammed into iPSCs. Furthermore, we measured the ATAD3A expression levels in the iPSCs to confirm the validity of these cell lines. The proband and her elder sister were both critically ill and harbored compound heterozygous ATAD3A variants (F459S/T498 Nfs* 13). Their parents were carriers of these variants without any clinical manifestations. Both variants are located on the ATPase domain of the ATAD3A protein. Cell lines ZJUCHYLi001-A and ZJUCHYLi002-A presented typical features of pluripotent stem cells. The ATAD3A expression levels of ZJUCHYLi001-A were significantly reduced compared with ZJUCHYLi002-A. This study generated iPSCs from a patient with compound heterozygous variants of ATAD3A and a negative control as valuable tools for clarifying the molecular mechanisms underlying ATAD3A variant-related diseases.