Abstract Background: 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. Methods: An 11-year-old patient with clinical features consistent with KCS2-like syndrome underwent whole exome sequencing, which identified a novel heterozygous variant in FAM111A gene. In vitroexperiments and protein structure analysis were performed to elucidate the contribution of this mutation to KCS2-like syndrome. Results: To confirm the diagnosis, whole exome sequencing revealed a novel heterozygous variant (c.405delA/p.E136Sfs*3) in FAM111A gene in an 11-year-oldpatient. 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 a 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. Conclusions: 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.
Wu et al. (Mon,) studied this question.