Submission Details

The relationship between the AGA gene and aspartylglucosaminuria (AGU), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of August 7, 2022. AGA encodes aspartylglucosaminidase, an enzyme involved in the breakdown of N-linked oligosaccharides of glycoproteins via cleaving asparagine from the N-acetylglucosamine (PMID: 1703489). Individuals with AGU show deficient aspartylglucosaminidase enzyme activity, leading to accumulation of aspartylglucosamine and other glycoasparagines in multiple tissues and in the urine (PMID: 8405810, PMID: 27906067), which results in the characteristic disease manifestations including progressive neurological impairment and skeletal and connective tissue anomalies (as reviewed in PMID: 27906067).

The disease mechanism of AGU is loss of function. AGU was first reported in 1967 by Jenner and Pollitt (Jenner, F. A., Pollitt, R. J. Large quantities of 2-acetamido-1-(beta-L-aspartamido)-1,2-dideoxyglucose in the urine of mentally retarded siblings. Biochem. J. 103: 48P-49P, 1967.) and 1968 by Pollitt et al. (PMID: 4173687) and the first reports of biallelic variants in AGA among cases with AGU in 1991 by Ikonen et al. (PMID: 1703489) and Fisher and Aronson (PMID: 1904874). Both case-level (genetic) and experimental evidence support the relationship between AGA and AGU. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 1703489, PMID: 1722323, PMID: 8830180, PMID: 7627186, PMID: 29247835, PMID: 11309371). In total, ten variants from eight probands in six publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached.

Experimental evidence for the relationship between AGA and AGU includes: the biochemical function of the gene product (aspartylglucosaminidase) being consistent with the clinical and biochemical findings identified individuals with AGU (PMID: 8405810, PMID: 27906067); the biochemical and clinical features of AGA knockout mice (PMID: 8946839); and rescue of systemic accumulation of mannose N-linked oligosaccharides via enzyme replacement therapy in AGA knockout mice (PMID: 20607610). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.

In sum, AGA is definitively associated with AGU. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on September 2, 2022 (SOP v9).