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This document summarizes the evidence linking mutations in ACP5 to spondyloenchondrodysplasia with immune dysregulation. The disorder is characterized by a variable skeletal dysplasia, neurological impairment, and a spectrum of immune abnormalities. Autosomal recessive inheritance is observed, with affected individuals manifesting spasticity, immunodeficiency, and autoimmunity. Multiple clinical studies have documented these features in patients from diverse ethnic backgrounds, highlighting the multisystem involvement in this condition. This association is supported by robust clinical observations that underline the penetrance and expressivity of the disorder.
Genetic evidence stems from numerous independent case reports and multi‐patient studies that consistently identify biallelic mutations in ACP5. Detailed molecular analyses have uncovered a wide spectrum of pathogenic variants, including missense, frameshift, splice‐site, and deletion mutations. For example, the variant c.130A>G (p.Thr44Ala) is one of several that has been reported in patients exhibiting typical clinical features (PMID:26346816). Segregation studies in consanguineous families further corroborate the autosomal recessive pattern, with additional affected relatives observed in multiple pedigrees. These convergent lines of evidence strongly support the causal role of ACP5 mutations in the disease phenotype.
A representative variant, c.130A>G (p.Thr44Ala), exemplifies the molecular disruption underlying the disorder. This variant, along with others documented in the literature, contributes to a deleterious loss of function in tartrate-resistant acid phosphatase (TRAP). Functional studies indicate that such mutations impair protein folding and abolish enzymatic activity, which in turn disrupts both bone remodeling and immune regulation. The variability of the mutations—from missense changes to frameshift events—has been systematically correlated with the phenotypic spectrum observed in affected individuals. The aggregation of these genetic findings across independent studies reinforces the pathogenic association.
Functional and experimental studies further delineate the mechanism of pathogenicity in spondyloenchondrodysplasia with immune dysregulation. Loss of TRAP activity is consistently demonstrated in both patient-derived samples and in vitro cell models. These experiments show that ACP5 mutations result in protein misfolding and reduced enzymatic function, leading to dysregulation of osteoclast activity and aberrant immune responses. In vitro assays and animal models recapitulate the skeletal and immune phenotypes, providing additional support for the disease mechanism (PMID:27390188). Such concordant experimental data validate the role of ACP5 in both bone metabolism and immune regulation.
Integration of genetic and experimental evidence provides a coherent narrative for the clinical association. Multiple independent studies have identified a broad variant spectrum in ACP5 that is consistently linked with the characteristic clinical features of spondyloenchondrodysplasia. The demonstration of loss of TRAP function in functional studies offers a mechanistic underpinning for the observed clinical manifestations. Although additional supportive evidence exists, the current body of literature reaches a clear consensus regarding the pathogenic role of ACP5 mutations. Overall, the evidence exceeds the maximum ClinGen scoring thresholds, reinforcing the clinical utility of this genetic marker.
In summary, the well‐documented association between ACP5 mutations and spondyloenchondrodysplasia with immune dysregulation is of high clinical utility. Clinicians and diagnostic laboratories should consider ACP5 screening in patients presenting with skeletal dysplasia combined with immune dysfunction. This integrated approach not only facilitates accurate diagnosis but also informs management strategies for affected individuals.
Key Take‐home message: Mutational analysis of ACP5 is essential for identifying spondyloenchondrodysplasia with immune dysregulation, enabling timely and targeted therapeutic interventions.
Gene–Disease AssociationStrongMultiple independent case reports with biallelic mutations identified in more than 20 probands (PMID:26346816), robust segregation in consanguineous families, and strong experimental concordance from functional studies (PMID:21217752). Genetic EvidenceStrongA diverse spectrum of pathogenic variants, including missense, frameshift, and splice-site mutations, have been reported in over 30 patients, with segregation analyses confirming autosomal recessive inheritance (PMID:26789720). Functional EvidenceModerateFunctional assays indicate that ACP5 mutations lead to loss of TRAP enzymatic activity and protein misfolding, which are consistent with the observed disruptions in bone turnover and immune regulation (PMID:27390188). |