Telomeres are hexanucleotide tandem repeats present at the ends of chromosomes which protect chromosomes from gradual degradation during cell division and aging. Once telomeres become critically shortened, the ends of chromosomes are exposed, which triggers the DNA damage response, p53 activation and apoptosis. For this reason, telomeres are referred to as molecular clocks.

Shortened telomere syndromes are clinically defined by premature loss of progenitor stem cells and reduced regenerative capacity of cells and organs. Organs with high cell turnover, such as bone marrow, liver, lungs and immune system are commonly affected. Clinical clues to a short telomere syndrome include premature graying of hair, cytopenia, hypogammaglobulinemia, cryptogenic cirrhosis and idiopathic pulmonary fibrosis.

Shortened telomere lengths are now believed to play an important role in a number of multisystem disorders including:

  • Bone marrow failure STSs
    • Dyskeratosis congenita
    • Hoyeraal-Hreidarsson syndrome
    • Reverz syndrome
    • Cerebroretinal microangiopathy with calcifications and cysts
    • Aplastic anemia
    • Fanconi anemia
  • Pulmonary STSs
    • Idiopathic pulmonary fibrosis
    • Familial lung fibrosis
    • Fibrotic idiopathic interstitial pneumonia
  • Gastrointestinal STSs
    • Cryptogenic cirrhosis
    • Nodular regenerative hyperplasia

The telomerase complex includes a reverse transcriptase encoded by TERT, RNA template encoded by TERC, along with other proteins that regulate the assembly of telomerase to telomeres and the stability of telomeres, including dyskerin (DKC1). Other members of the telomerase complex include NOP10 (NOLA3) and NHP2 (NOLA2). Shelterin is a 6-protein complex that coats telomeres and offers telomere end protection. DNA helicase, RTEL1 promotes telomere elongation through the unwinding of the T-loop. TCAB1 (WRAP53) directs trafficking of the telomerase complex to the telomeric ends. The CST complex of 3 proteins (CTC1 and others) inhibits telomerase activity and promotes capping.

Telomere biology disorders can be inherited in a variety of patterns, including X-linked recessive, autosomal dominant, and autosomal recessive. Short telomere syndromes have been associated with mutations in the following genes: ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, ZCCHC8

At least 50% of patients with dyskeratosis congenita have mutations in the DKC1, TERC, TERT, TINF2, NHP2, and NOP10 genes. In autosomal dominant dyskeratosis congenita, patients may develop symptoms at a younger age and show more severe disease in successive generations.

Bone marrow disorders have been associated with mutations in the following genes:

Thrombocytopenia

Genes: ACTN1, ANKRD26, CYCS, ETV6, FLI1, FLNA, FYB, GATA1, GATA2, GFI1B, GP1BA, GP1BB, GP9, HOXA11, ITGA2B, ITGB3, LYST, MPL, MYH9, NBEAL2, PRKACG, RBM8A, RUNX1, SLFN14, SRC, TUBB1, VWF, WAS

Myelodysplastic syndrome and acute leukemia

Genes: ANKRD26, CEBPA, DDX41, ETV6, GATA2, IKZF1, PAX5, RUNX1, SAMD9, SAMD9L, SRP72, TP53

Familial MPN

Genes: JAK2, RBBP6, THPO

Diamond-Blackfan Anemia and DBA-like hypoplastic anemias

Genes: CECR1, EPO, GATA1, MYSM1, RPL11, RPL15, RPL18, RPL26, RPL27, RPL31, RPL35, RPL35A, RPL5, RPS10, RPS15A, RPS17, RPS19, RPS24, RPS26, RPS27, RPS28, RPS29, RPS7, TSR2

Fanconi anemia

Genes: BRCA1, BRCA2, BRIP1, ERCC4, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MAD2L2, PALB2, RAD51, RAD51C, RFWD3, SLX4, UBE2T, XRCC2

Severe congenital neutropenia

Genes: CSF3R, CXCR4, ELANE, G6PC3, GFI1, HAX1, JAGN1, TAZ, USB1, VPS45, WAS

Sideroblastic anemia

Genes: ABCB7, ALAS2, GLRX5, PUS1, SLC19A2, SLC25A38, TRNT1, YARS2

Additional genes: ATM, BLM, C15ORF41, CBL, CHEK2, DNAJC21, EFL1, EPCAM, ERCC6L2, LIG4, LYST, MLH1, MPL, MSH2, MSH6, NBN, NF1, PMS2, PTPN11, RAB27A, RBM8A, SBDS, SLC19A2, SLC37A4, SRP54, VPS13B, YARS2

Specimen requirement is 3 to 6mL of whole blood in EDTA (lavendar topped tube) or saliva collected in an appropriate collection device (Oragene®-DNA 500 or 600 device)

Johns Hopkins University offers a test called MarrowZoom in which telomere gene mutations are detected by next generation sequencing. Testing currently costs about $3000 and is not covered by insurance.  

References

Mangaonkar AA and Patnaik MM, Short Telomere Syndromes in Clinical Practice: Bridging Bench and Bedside. Mayo Clin Proc 2018;93:904-16.

https://www.hopkinsmedicine.org/dnadiagnostic/tests/tests/marrowzoom


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