Cerebroretinal Microangiopathy with Calcifications and Cysts (Coats plus syndrome) via the CTC1 Gene

Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is a multisystem disorder particularly affecting the eye, brain, bone and gastrointestinal tract. It is also known as Coats plus syndrome due to the presence of presence of bilateral retinal telangiectasia and exudates (Coats disease), cerebral calcification, leukoencephalopathy, slow pre- and post-natal linear growth and defects of bone marrow and integument (Crow et al. 2004; Linnankivi et al. 2006).

CRMCC is an autosomal recessive disorder, which is caused by pathogenic variants in CTC1 gene. CTC protein is a member of the CTC1–STN1–TEN1 (CST) complex, which is critical for telomere replication. This explains the presence of critically shortened telomeres in CRMCC patients, and suggests that telomere dysfunction plays a key role in CRMCC pathogenesis (Gu and Chang 2013). So far, over 25 causative variants (missense, nonsense, splicing, small deletions and insertions) have been reported to be causative in CTC1 (Human Gene Mutation Database).

A mutation screening in 10 CRMCC patients found that all patients were compound heterozygous for CTC1 pathogenic variants (Anderson et al. 2012). In another study in 15 CRMCC-Affected Individuals, 13 patients were compound heterozygous for CTC1 pathogenic variants (Polvi et al. 2012). These studies suggest that the clinical sensitivity is high. Analytical sensitivity should be high as well because all the reported CTC1 causative variants are detectable by sequencing.

This test provides full coverage of all coding exons of the CTC1 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).