Submission Details

ACY1 was first reported in relation to Autosomal Recessive Aminoacylase 1 Deficiency in 2005 (Van Coster et al., PMID: 16274666). At least 10 unique variants, most of which are missense or null, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 14 probands in seven publications (PMIDs: 24997716, 24117009, 16465618, 17562838, 21414403, 16274666, 20480396). All of these probands share the common biochemical abnormality of organic aciduria and have confirmatory verification of deficent aminoacylase activity in fibroblasts or lymphocytes. Other phenotypes are observed in individual probands, such as psychomotor delay, hypotonia, and seizures, however the presence of asymptomatic probands indicates these phenotypes may or may not be associated with the biochemical abnormality. The mechanism for disease is biallelic loss of function, with significantly reduced or absent aminoacylase activity causing accumulation of acylated amino acids in the tissues and urine. This gene-disease association is also supported by the protein's biological function and functional studies in E. coli, demonstrating that mutant proteins have significantly impacted catalytic activity when compared to the wild-type. No animal models for this abnormality have been published at this time. In summary, ACY1 is definitively associated with autosomal recessive aminoacylase 1 deficiency. This has been repeatedly demonstrated in the clinical diagnostic setting and has been upheld over time.