A Novel FAM111A Frameshift Variant Associated With Osteoclast Necroptosis and KCS2-like Syndrome.

Kenny-Caffey syndrome type II (KCS2) is a rare genetic disorder characterized by skeletal abnormalities, impaired growth, and developmental delay. This study investigates a novel heterozygous FAM111A variant's role in a patient presenting with KCS2-like features. An 11-year-old patient with clinical features consistent with KCS2-like syndrome underwent whole exome sequencing, which identified a novel heterozygous variant in the FAM111A gene. In vitro experiments and protein structure analysis were performed to elucidate the contribution of this mutation to KCS2-like syndrome. To confirm the diagnosis, whole exome sequencing revealed a novel heterozygous variant (c.405delA/p.E136Sfs*3) in the FAM111A gene in an 11-year-old patient. Additionally, we found the clinical features of this patient were consistent with KCS2-like syndrome. Our in vitro studies revealed that the variant led to a significant increase in necroptosis of osteoclasts. Furthermore, variant osteoclasts displayed a significant down-regulation of autophagy, which may contribute to the onset of KCS2-like syndrome. Consequently, the augmented necroptosis may result in the up-regulation of inflammatory cytokines such as IL-1β, IL-17, IL-12p70, MCP-1, IFN-γ and TNF-α. Protein structure analysis suggests that the truncated FAM111A (p.E136Sfs*3) retains an ubiquitin-like domain, which might explain the up-regulated ubiquitination in variant osteoclasts. Therefore, the enhanced ubiquitination in variant osteoclasts may lead to the excessive degradation of intracellular proteins, resulting in irreversible necroptosis. Our findings suggest that the novel variant FAM111A (c.405delA) may be a pathogenic factor in KCS2-like syndrome, likely through mechanisms involving increased necroptosis and inflammation. This expands understanding of FAM111A variant's role in skeletal and immune dysregulation.