Abstract
BackgroundThe telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKC), the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs.MethodsClinical sequencing was performed on a cohort of patients presenting with variable immune phenotypes lacking molecular diagnoses. Hypothesis-free whole-exome sequencing (WES) was selected in the absence of compelling diagnostic hints in patients with variable immunological and haematological conditions.ResultsIn four patients belonging to three families, we have detected five novel variants in known TBD-causing genes (DKC1, TERT and RTEL1). In addition to the molecular findings, they all presented shortened blood cell telomeres. These findings are consistent with the displayed TBD phenotypes, addressing towards the molecular diagnosis and subsequent clinical follow-up of the patients.ConclusionsOur results strongly support the utility of WES-based approaches for routine genetic diagnostics of TBD patients with heterogeneous or atypical clinical presentation who otherwise might remain undiagnosed.
Highlights
The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure
We considered only variants with a minor allele frequency (MAF) < 0.01, with frequency filtering based on data from Genome Aggregation Database
Patient 1 (P1.1) is a 24-year-old male from a non-consanguineous family. He was remitted to whole-exome sequencing (WES) to search for mutations associated with chronic mucocutaneous candidiasis, with the identification of a novel variant in Dyskerin Pseudouridine Synthase 1 (DKC1) (c.1218_1219insCAG, p.(Asp406_Ser407insGln))
Summary
The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs. The telomere biology disorders (TBDs), or telomeropathies, embody a range of pathological phenotypes ensuing from abnormal telomerase function. The first TBD to be described was dyskeratosis congenita (DKC), a severe inherited multisystem disorder characterized by reticulate skin pigmentation, nail dystrophy, oral leukoplakia and bone marrow failure, presenting with cytopenia of one or more hematopoietic cell lineages [1]. A severe variant of DKC manifests as Hoyeraal-Hreidarsson syndrome (HHS) This is a rare disorder characterized by bone marrow failure, immunodeficiency, cerebral hypoplasia and intra-uterine growth retardation [3, 7]. Exact genetic diagnosis in DKC is essential due to the limited efficacy of therapeutic options, and the genetic anticipation common in DKC makes timely family counseling a priority
Sign-in/Register to view highlights & summary 
Published Version (
Free)
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