STN1

Inheritance Pattern: AR

Disease ID:MONDO:0015026

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0015026

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0012815

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0015026

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0015026

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0015026

Submitter: ClinGen

STN1 was first reported in relation to autosomal recessive Coats plus syndrome in 2016 (Simon et al., PMID 27432940), which has also been called cerebroretinal microangiopathy with calcifications and cysts 2 (CRMCC2). Both conditions are characterized by retinal telangiectasia and exudates (Coats disease), leukodystrophy and brain cysts, osteopenia with a tendency to fractures and poor bone healing, and a high risk of life-limiting gastrointestinal bleeding caused by vasculature ectasias in the stomach, small intestine and liver (PMID: 22267198). The STN1 gene encodes STN1 subunit of CST Complex, which functions in a telomere-associated complex with CTC1 and TEN1. The CST complex appears to protect telomeres by inhibiting telomerase activity (PMID 2276344). Coats plus has also been associated with biallelic variants in CTC1 (PMIDs: 22387016, 22267198, 22532422, 30891747). Variants in STN1 have been reported in individuals with the following disease entities: Coats plus syndrome, Cerebroretinal microangiopathy with calcifications and cysts 2 (CRMCC2). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanisms or inheritance pattern; furthermore we found that the spectrum of phenotypic variability could exist between the described disease entities. Therefore, Coats Plus and CRMCC2 have been lumped into one disease entity, CRMCC2 (MONDO:0015026), also known as STN1-related telomere biology disorder. Six variants (missense, nonsense, frameshift) that have been reported in at least four probands in three publications are included in this curation (27432940, 34110109, 32627942). The mechanism of pathogenicity is known to be loss of function (Simon et al., 27432940). This gene-disease relationship is supported by animal models, biochemical function, protein interaction, functional alteration of patient cells (PMIDs 27432940, 19854130, 22964711). A zebrafish STN1-knockdown model demonstrated a similar phenotype to humans with biallelic STN1 variants, with the zebrafish exhibiting telangiectasias and anemia (27432940). Patient fibroblasts when compared to control fibroblasts demonstrated significantly decreased population doublings, however when introduced to exogenous WT STN1 the patient fibroblasts were able to increase population doublings (27432940). STN1 is known to coimmunoprecipitate with CTC1, which has already been implicated in Coats plus (19854130). Finally, it is known that STN1 shares a similar role to CTC1 in that it protects telomeres; when STN1 was knocked down in HeLa cells, there was an increase in telomere breakage, which has also been demonstrated in cells with CTC1 knockdown (22964711, 22531781). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy Gene Curation Expert Panel on the meeting date 4/27/26 (SOP Version 12).