Submission Details

The relationship between ASPA and Canavan disease was evaluated using the ClinGen Clinical Validity Framework as of September 16, 2020. Canavan disease is an autosomal recessive leukodystrophy, characterized by fatal spongiform encephalopathy of the brain. For most affected patients, onset of symptoms occurs in the first months of life, with hypotonia, macrocephaly, developmental delays, and seizures. These children usually pass away in early childhood. Later onset, milder forms of the condition have also been described (Matalon et al, 2018, PMID 20301412). Canavan disease is most prevalent in individuals of Ashkenazi Jewish descent, but has been reported in individuals of many different ethnicities (Matalon et al, 2018, PMID 20301412). ASPA, the gene implicated in Canavan disease, encodes aspartoacylase, an enzyme that converts N-acetylaspartic acid (NAA) into acetate and aspartic acid. In patients with Canavan disease, NAA is elevated in patient urine and blood. The disease mechanism is loss of function. Biallelic variants in ASPA were first reported in patients with Canavan disease in 1993 (Kaul et al, PMID 8252036). Since then, about 70 variants in ASPA have been associated with Canavan disease (https://databases.lovd.nl/shared/variants/ASPA/unique), including two variants, p.Gla285Ala and p.Tyr231Ter, that together account for 98% of alleles in Ashkenazi Jewish patients, and another variant, p.Ala305Glu, that accounts for 30-60% of alleles in non-Jewish patients (Matalon et al, 2018, PMID 20301412). The relationship between ASPA and Canavan disease is supported by case-level and experimental evidence. Sixteen unique variants (missense, frameshift, and nonsense) in 16 probands from 7 publications were curated (Kaul et al, 1993, PMID 8252036; Kaul et al, 1994, PMID 8023850; Kaul et al, 1996, PMID 8659549; Zen et al, 2002, PMID 12638939; Janson et al, 2006, PMID 16437572; Mendes et al, 2017, PMID 28101991; Froukh, 2019, PMID 30834272). Further information is available in the literature but the maximum score for genetic evidence (12 points) has been reached. Experimental evidence supporting this gene-disease relationship includes the biochemical function of ASPA, which is consistent with the biochemical findings and disease process in patients (Kaul et al, 1991, PMID 1987315; Kaul et al 1993, PMID 8252036; Hoshino and Kubota et al, 2014, PMID 24977939 von Jonquieres et al, 2018, PMID 29116375), the features of a mouse model, Deaf14, which is homozygous for a nonsense variant in Aspa (Carpinelli et al, 2014, PMID 24682784), and gene therapy studies in mice and humans (Leone et al, 2012, PMID 23253610; Carpanelli et al, 2014, PMID 24682784). Further evidence is available in the literature but the maximum score for experimental evidence (6 points) has been reached. In summary, ASPA is definitively associated with Canavan disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.