A Multi-Center Integrative Cohort Characterizing the Genetic, Clinical, and Transcriptomic Features of ACP5 Deficiency.

Biallelic ACP5 variants with loss of tartrate-resistant acid phosphatase (TRAP) activity; type I interferon signature, monocytes a major source of inflammation.

Multi-centre integrative cohort of 17 patients with ACP5 deficiency (SPENCDI) from Egypt and China, with five novel pathogenic variants, including three missense confirmed by loss of TRAP activity. Skeletal involvement dominates (dysplasia, short stature), with high inflammatory activity. The transcriptome (bulk and single-cell) reveals enrichment of NF-κB, MAPK and cell-death pathways and a type I interferon signature in monocytes, identified as a major source of inflammation. Therapeutically, prednisolone and azathioprine were most effective, with a partial response to JAK inhibitors (ruxolitinib, upadacitinib).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Beyond expanding the ACP5 spectrum, the value is the interferonopathy/monocyte mechanistic link that rationalises a therapeutic lead (JAK inhibitors), even if the response is only partial here. The functional confirmation of missense variants by TRAP activity is a good example of anchoring variant classification. A modest but well-phenotyped cohort.

Analysis by Dr Thibaut Benquey