Submission Details

The relationship between the CTSA gene and galactosialidosis (GSL), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of August 4, 2022. CTSA encodes cathepsin A (aka protective protein) (PMID: 3136930), a multifunctional enzyme that acts as part of the lysosome multifunctional complex to stabilize lysosomal β-galactosidase (GAL), and activate the lysosomal sialidase Neu1 (PMID: 6812049). Individuals with GSL show combined β-galactosidase (GAL) and Neu1 deficiency (PMID: 6812049) due to reduced cathepsin A activity (PMID: 8725271), leading to characteristic clinical features including coarse facies, macular cherry red spots, and skeletal dysostosis (PMID: 28603679).

Prenatal presentation: Biallelic variants in CTSA lead to Galactosialidosis with phenotypic variability. The severe presentation, often referred to as “early infantile” is characterized prenatally by non-immune hydrops fetalis and is often associated with pre or perinatal lethality. Individuals with either biallelic variants in CTSA or a biochemical diagnosis of Galactosialidosis and relevant prenatal phenotypes have been described in multiple publications with nonsense, frameshift and missense variants described (PMID: 7759227; 8838767; 19466716; 16674934; 23915561; 26036949).

The disease mechanism of GSL is loss of function. GSL was first reported in 1971 by Goldberg et al. (PMID: 4999185) and the first reports of biallelic variants in CTSA among GSL cases in 1991 by Takano et al. (Takano, T., Shimmoto, M., Fukuhara, Y., Itoh, K., et al. (1991). Galactosialidosis: Clinical and molecular analysis of 19 Japanese patients. Brain Dysfunction, 4(5), 271–280.) Both case-level (genetic) and experimental evidence support the relationship between CTSA and GSL. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 24769197, PMID: 28555253, PMID: 15110321, PMID: 9603439, PMID: 8514852, PMID: 8968752, PMID: 27243974). In total, thirteen variants from seven 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 CTSA and GSL includes: the biochemical function of the gene product (cathepsin A) being consistent with the clinical and biochemical findings identified individuals with GSL (PMID: 6812049, PMID: 8725271, PMID: 28603679); the biochemical and clinical features of CTSA knockout mice (PMID: 7590240); and rescue of enzyme function via allogenic bone marrow transplantation in CTSA knockout mice (PMID: 7590240). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.

In sum, CTSA is definitively associated with GSL. 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).