Submission Details

The CTNS gene is located on chromosome 17 at p13.2 and encodes cystinosin, a seven-transmembrane domain protein expressed on lysosomal membranes. Cystinosin functions to transport cystine, a by-product of lysosomal protein hydrolysis, out of lysosomes and into the cytoplasm where it is reduced to cysteine. In the absence of a functional cystinosin protein, cystine accumulates and crystallizes in the lysosomal lumen.

Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their molecular mechanisms, inheritance pattern or phenotypic spectrum. Therefore, the following disease entities have been lumped into one disease entity: Cystinosis, nephropathic (OMIM:219800); Cystinosis, late-onset juvenile or adolescent nephropathic (OMIM:219900); and Cystinosis, ocular non-nephropathic (OMIM:219750). The preferred disease name suggested for this grouping of disorders is ‘Cystinosis - CTNS’.

CTNS was first reported in relation to autosomal recessive cystinosis in 1998 (Town et al., PMID: 9537412). In the most frequent form, infantile nephropathic cystinosis, individuals typically present during the second half of the first year of life, with short stature and failure to thrive, renal Fanconi syndrome, hypophosphatemic/calcipenic rickets, and corneal crystals that eventually cause photophobia. Left untreated, kidney function will continue to deteriorate, eventually progressing to kidney failure at 10-12 years of age. Adult-onset, ocular non-nephropathic cystinosis is characterized solely by corneal cystine crystal accumulation. The mechanism of pathogenicity for cystinosis is known to be loss of function, with milder phenotypes generally associated with mutant cystinosin that retains some residual function (PMID: 15128704). The exact mechanisms that cause clinical symptoms remain incompletely understood, but cystine crystal accumulation, macrophage activation, enhanced oxidative stress, and inflammasome pathway activation are all driving factors (PMID: 35053306).

More than 150 pathogenic variants (missense, nonsense, splice altering variants, small indels, promoter variants, and large deletions), located throughout the gene, have been reported (summarized in PMID: 30554218). Of note, a 57kb deletion accounts for 50% of mutant alleles in patients of Northern European ancestry, with the following variants also recognised as founder/recurrent variants in certain populations: c.1015G>A, c.971–12G>A, c.681G>A, and c.414G>A. A total of 9 variants identified in 8 probands over 8 publications are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data.

This gene-disease relationship is also supported by animal models that recapitulate the human phenotype. A FVB/N knockout mouse model showed accumulation of cystine in all organs tested, with mice also developing ocular changes and bone defects (PMID: 12370309). A C57BL/6 knockout mouse model showed accumulation of cystine in multiple organs, as well as proximal tubulopathy, focal tubular lesions, and progressively developed chronic renal failure (PMID: 19846395). A knock in zebrafish model of a homozygous nonsense mutation showed cystine accumulation, impaired glomerular permselectivity and defective tubular reabsorption, with podocytes showing partial foot process effacement and narrowed slit diaphragmatic space (PMID: 28198397). A total of 5/6 pts. for experimental evidence was reached.

In summary, there is definitive evidence supporting the relationship between CTNS and autosomal recessive cystinosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.