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The association between ACP4 and amelogenesis imperfecta (MONDO_0019507) is supported by multiple lines of evidence. Two independent families were reported in a case study where biallelic ACP4 mutations segregated with the hypoplastic form of the disease. In one family, distinct paternal and maternal mutations were identified, while in the second family, a de novo mutation in trans with another variant was reported (PMID:34036831).
These findings are consistent with an autosomal recessive mode of inheritance. Detailed genetic analyses revealed four pathogenic variants, with one being reported as c.350A>G (p.Gln117Arg). Additional multi‐patient studies utilizing next‑generation sequencing have also implicated ACP4 in amelogenesis imperfecta, thereby reinforcing the gene–disease association (PMID:37228816).
Genetic evidence is further bolstered by the recurrence of distinct mutation types across families, and the segregation pattern supports a recessive model. Although the overall number of probands is modest, the consistency across independently ascertained families substantially strengthens the association with the disease.
Functional studies have provided mechanistic insights: in vitro assays demonstrated that mutant ACP4 proteins exhibit reduced protein expression, impaired homodimer formation, and a notable decrease in acid phosphatase activity. These experimental findings are consistent with a loss‑of‑function mechanism that mirrors the enamel formation defects observed in affected individuals (PMID:28513613).
Integrating the genetic and functional evidence reveals a coherent narrative where biallelic ACP4 mutations compromise protein function, leading to enamel hypoplasia. The evidence, while robust, likely exceeds the threshold for maximum ClinGen scoring, supporting its clinical use in the diagnostic workup of amelogenesis imperfecta.
Key take‑home sentence: ACP4 should be considered a strong candidate gene in patients with hypoplastic amelogenesis imperfecta, warranting its inclusion in genetic diagnostic panels to facilitate precise clinical management.
Gene–Disease AssociationStrongTwo independent families with biallelic ACP4 variants and supportive multi‑patient data provide robust evidence for the association (PMID:34036831, PMID:37228816). Genetic EvidenceStrongFour distinct pathogenic variants identified across two families, consistent with autosomal recessive segregation, support the genetic link. Functional EvidenceModerateIn vitro analyses reveal decreased protein expression, impaired homodimerization, and reduced acid phosphatase activity, aligning with a loss‑of‑function pathogenic mechanism (PMID:28513613). |