CTC1

Inheritance Pattern: AR

Disease ID:MONDO:0012815

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0015780

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0015780

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0024564

Submitter: ClinGen

CTC1 was first reported in relation to autosomal recessive Coats Plus syndrome in 2012 (Anderson et al., PMID: 22267198). Characteristic features of Coats Plus include 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). In the same year, another group published a cohort of patients with cerebroretinal microangiopathy with calcifications and cysts 1 (CRMCC1; PMID 22387016). This cohort presented with very similar features to those in the Coats Plus cohort. Bilallelic variants in CTC1 have also been published in two individuals described as having Dyskeratosis congenita, which is a bone marrow failure syndrome with elevated cancer risk (PMIDs 22532422, 32543263); one proband also had intracranial calcifications (PMID 32543263). The CTC1 gene encodes CST telomere replication complex component 1, which functions in a telomere-associated complex with STN1 and TEN1. The CST complex protects telomeres by inhibiting telomerase activity (PMID 22763445). Patients presenting with these phenotypes have been found to have short telomeres (PMID 30891747). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern across the three aforementioned disease entities; furthermore we found that the spectrum of phenotypic variability could exist between the described disease entities. Therefore, these disease entities have been lumped into a single disease entity CRMCC1 (MONDO:0024564), also known as CTC1-related telomere biology disorder . This curation includes ten variants (missense, in-frame indel, frameshift) that have been reported in eight probands in four publications (PMIDs: 22387016, 22267198, 22532422, 30891747). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is supported by a mouse model (PMID: 22531781). In this study, CTC1 knockout mice demonstrated complete bone marrow failure that likely led to their premature death. This phenotype was observed in some patients described with bone marrow failure and CTC1 biallelic variants. In summary, there is definitive evidence supporting the relationship between CTC1 and autosomal recessive CRMCC1, with the preferred name of CTC1-related telomere biology disorder. Two other GCEPs contributed to this curation: The Childhood, Adolescent and Young Adult Cancer (CAYA) GCEP and the Interstitial Lung Disease (ILD) GCEP. The CAYA GCEP found that although there were no reported cases of leukemia or other malignancies in patients with CTC1 variants, telomere-biology disorders generally imply elevated cancer risk. The ILD GCEP noted cases of pulmonary involvement, but insufficient evidence to split out an isolated pulmonary disease from the curated disease entity from the lumped group of disease entities. This gene-disease relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date November 12, 2025 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0024564

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0024564

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0024564

Submitter: G2P