A Multicenter Integrative Cohort Characterizing the Genetic, Clinical, and Transcriptomic Features of ACP5 Deficiency

Area of Science:

• Genetics and immunology
• Rare disease research
• Molecular biology

Background:

• Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is a rare genetic disorder.
• It is caused by biallelic mutations in the ACP5 gene.
• Understanding its genetic and clinical spectrum is crucial for diagnosis and treatment.

Purpose of the Study:

• To systematically evaluate the genetic landscape, clinical features, treatment outcomes, and transcriptomic alterations in SPENCDI.
• To identify novel pathogenic variants in ACP5.
• To elucidate the underlying immune dysregulation mechanisms.

Main Methods:

• Whole-exome sequencing for genetic diagnosis.
• Measurement of tartrate-resistant acid phosphatase (TRAP) activity.
• Integration of existing and new patient data for comprehensive analysis.
• Bulk and single-cell RNA sequencing to investigate immune signaling pathways.

Main Results:

• Identified 17 patients with ACP5 deficiency, including five novel pathogenic variants.
• Predominant clinical features include skeletal dysplasia and short stature.
• Revealed elevated inflammatory activity with enrichment of NF-κB, MAPK, and cell death pathways, and upregulation of type I interferon genes in monocytes.
• Observed enhanced IFN-γ signaling between monocytes and Natural Killer cells.
• Prednisolone and Azathioprine showed efficacy, while JAK inhibitors provided partial response.

Conclusions:

• Expanded the known genetic and clinical spectrum of ACP5 deficiency.
• Identified an upregulated interferon signature and highlighted monocytes as a primary source of inflammation.
• Provided valuable insights for improving SPENCDI diagnosis and treatment strategies.