PROJECT SUMMARY Individuals with rare genetic diseases do not receive attention from the medical and research community. One out of two patients diagnosed with a rare disease is a child, meaning that patients and their families must endure long battles relating to disease progress throughout their child’s lifetime. Therefore, characterization of clinical/molecular aspects of rare diseases will greatly benefit young patients and their families. SON is a DNA- and RNA-binding protein that plays dual roles as an RNA splicing factor and a transcriptional repressor. Our research team recently identified Zhu-Tokita-Takenouchi-Kim syndrome (ZTTK syndrome), a rare genetic disease with multi-organ abnormalities caused by heterozygous loss-of-function mutations in the SON gene (SON haploinsufficiency). Our research and publication played a key role in documenting this syndrome in major public databases to facilitate clinical diagnosis. As a first step in supporting ZTTK families and promoting awareness, we recently launched an official foundation, the ZTTK SON-Shine Foundation. Our recent efforts revealed that many children with ZTTK syndrome experience various hematopoietic disorders and immune dysfunction, which sometimes leads to life-threatening sepsis. To understand the hematopoietic abnormalities associated with ZTTK syndrome, we have generated mouse models of Son knockout (KO) and Son haploinsufficiency. Our preliminary data demonstrated that complete Son KO in hematopoietic cells causes hematopoietic stem cell (HSC) expansion and embryonic lethality. Furthermore, we found that Son haploinsufficiency leads to abnormal proportions of lineage-primed multipotent progenitors (MPPs), with an expansion of megakaryocyte-erythroid lineage-primed MPPs and a shrinkage of lymphoid lineage-primed MPPs, which is already evident during fetal liver hematopoiesis and persists in adult hematopoiesis in the bone marrow. Importantly, our RNA-sequencing analyses revealed that critical chro