Abstract
Dyskeratosis congenita (DKC) is associated with impaired telomere maintenance and with clinical features of premature aging. In this study, we analysed global DNA methylation (DNAm) profiles of DKC patients. Age-associated DNAm changes were not generally accelerated in DKC, but there were significant differences to DNAm patterns of healthy controls, particularly in CpG sites related to an internal promoter region of PR domain containing 8 (PRDM8). Notably, the same genomic region was also hypermethylated in aplastic anemia (AA) – another bone marrow failure syndrome. Site-specific analysis of DNAm level in PRDM8 with pyrosequencing and MassARRAY validated aberrant hypermethylation in 11 DKC patients and 27 AA patients. Telomere length, measured by flow-FISH, did not directly correlate with DNAm in PRDM8. Therefore the two methods may be complementary to also identify patients with still normal telomere length. In conclusion, blood of DKC patients reveals aberrant DNAm patterns, albeit age-associated DNAm patterns are not generally accelerated. Aberrant hypermethylation is particularly observed in PRDM8 and this may support identification and classification of bone marrow failure syndromes.
Highlights
Dyskeratosis congenita (DKC) is a rare disease that is often associated with mutations in genes required for proper telomere maintenance (e.g. DKC1, TERT, RTEL1, TIN2, TERC) [1, 2]
We utilized two models for epigenetic age-predictions: a www.impactjournals.com/oncotarget model developed by Horvath that is based on DNA methylation (DNAm) at 353 age-associated CpG dinucleotides [13], and our previously published model based on 99 age-associated CpGs [12, 14][]
The epigenetic age-predictions did not demonstrate general acceleration of age-associated DNAm (Figure 1). This was unexpected, as we previously observed overestimation of biological age using an epigenetic signature based on only three age-associated CpG sites [12]. This discrepancy may partly be attributed to the fact that the linear model for the three-CpGSignature has not been trained for young donors and to the possibility that only specific CpGs reveal aberrant DNAm in DKC
Summary
Dyskeratosis congenita (DKC) is a rare disease that is often associated with mutations in genes required for proper telomere maintenance (e.g. DKC1, TERT, RTEL1, TIN2, TERC) [1, 2]. Diagnosis of DKC necessitates awareness in the clinic, and appropriate laboratory testing of telomere length (TL; usually below the 1% percentile) and genetic sequencing [5, 6]. Not all DKC patients reveal dramatically shortened telomeres [7] and clinically relevant mutations are not always to be found [8]. Correct diagnosis of DKC and AA is important for adequate treatment and more specific biomarkers are urgently wanted [4]. Specific DNA methylation (DNAm) changes are indicative for diagnosis, prognosis, choice of therapeutic regimen in many diseases [11]. We analyzed DNAm profiles of DKC patients to further clarify if age-associated DNAm changes are enhanced in this disease [12] and if aberrant DNAm patterns can be used to support diagnosis of DKC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
