CTC1 Mutations in a patient with dyskeratosis congenita

Abstract

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome caused by mutations in seven genes involved in telomere biology, with approximately 50% of cases remaining genetically uncharacterized. We report a patient with classic DC carrying a compound heterozygous mutation in the CTC1 (conserved telomere maintenance component 1) gene, which has recently implicated in the pleiotropic syndrome Coats plus. This report confirms a molecular link between DC and Coats plus and expands the genotype-phenotype complexity observed in telomere-related genetic disorders.

Fig. 1

A: Skin and oral mucosal manifestations in our patient with DC and CTC1 mutations. B: Bone marrow biopsy showing a markedly hypocellular marrow with rare hematopoietic elements. C: Measurement of telomere length by flow-cytometry/fluorescence in situ hybridization (flow-FISH) in lymphocytes (left) and granulocytes (right), plotted as percentile of age-adjusted normal values. D: Retinal photograph showing a normal posterior pole (left panel), but obliterated (black arrows) and sheathed (blue arrow) vessels in the temporal fundus periphery (right panel). Findings were similar bilaterally.

Fig. 2

A: Sanger sequencing of CTC1 exons 5 (upper panel) and exon 18 (lower panel) on DNA from peripheral blood cells. The 5’ site of each deletion junction is indicated (red arrow), and the residues deleted on one allele are shown (red box). The normal sequence and resulting mutant allele sequence are depicted. B: Compared to normal fibroblasts (left panel), patient fibroblasts showed several features of senescence including frequent polygonal forms, ballooning, dendritic-like projections and degeneration(17, 18) (middle and right panels). C: Neuroimaging. Left panel: Cranial axial computed tomography (CT) scan showing right-sided thalamic calcification (red arrow). Right panel: cervical spine sagittal T2 magnetic resonance imaging (MRI) showing extensive septated syrinx in cervical to thoracic portions of spinal cord (demarcated by blue line).