Galactosialidosis via the CTSA Gene

Galactosialidosis (GSL) is a rare lysosomal storage disease characterized by combined deficiency of beta-galactosidase and neuraminidase 1, secondary to deficiency of the protective protein/cathepsin A (PPCA/CTSA). Clinically, there are three subtypes of GSL: early infantile, late infantile, and juvenile/adult. All three subtypes have characteristic features of a lysosomal storage disease including coarse facies and cherry red spots. The most severe form, early infantile, is characterized by hydrops fetalis, edema, ascites, visceromegaly, skeletal dysplasia, and early death. The late infantile form is characterized by cardiac anomalies, visceromegaly, and, in rare cases, neurological involvement. The least severe form, juvenile/adult, is characterized by ataxia, myoclonus, absence of visceromegaly, intellectual disability, growth retardation, and long survival (Caciotti et al. 2013; Prada et al. 2014; Shamseldin et al. 2015; Zhou et al. 1996).

GSL is caused by variants in the cathepsin A (CTSA) gene and is inherited in an autosomal recessive fashion. To date, about 30 pathogenic variants have been reported in CTSA, including missense, nonsense, splicing, small deletions, and small duplications (Human Gene Mutation Database). Functional studies have suggested that the severity of disease may correlate with the impact of specific variants on PPCA/CTSA protein function, with the more severe phenotype being associated with a greater reduction in the catalytic and regulatory/protective functions of the protein (Caciotti et al. 2013; Zhou et al. 1996).

Given the rarity of GLS, no large scale studies have been performed to determine the clinical sensitivity of CTSA gene testing in these patients. However, given the characteristic biochemical features of the disorder (deficiency of beta-galactosidase and neuraminidase 1), it is expected that clinical sensitivity would be high in patients with biochemical evidence of GLS (Caciotti et al. 2013).

This test provides full coverage of all coding exons of the CTSA gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).