Telomere biology disorders: ends and (genetic) means

In this issue of Blood, Niewisch et al¹ analyzed the clinical features and outcomes associated with different germline genotypes of telomere biology disorders (TBDs). This study highlights the presentation and clinical implications of TBDs across all ages.

Telomeres are the specialized structures at the ends of chromosomes composed of repetitive DNA sequences complexed with proteins to protect free DNA ends and maintain genomic stability. TBDs are variably characterized by bone marrow failure, cancer predisposition, and multiorgan system complications, particularly liver fibrosis or cirrhosis and pulmonary fibrosis. Although the availability of genetic testing and telomere length testing has rapidly advanced the diagnosis of TBDs,² the variable phenotypes of TBDs pose significant challenges to prospective medical management. The development of evidence-based strategies for tailored clinical care is challenging for rare diseases. One standard approach for risk stratification is to analyze clinical outcomes based on the causative gene; however, certain TBD genes may cause disease with either heterozygous or biallelic mutations. To account for this allelic complexity, this study analyzed outcomes over time for 200 patients based on both genotype and inheritance pattern: recessive (DKC1, 32; RTEL1, 15; CTC1, 6; PARN, 4; WRAP53, 3; TERT, 2; ACD, 2), dominant/heterozygous (TERT, 47; TERC, 30; RTEL1, 29; PARN, 4; ACD, 1), and de novo/dominant (TINF2, 25).

Consistent with previous reports, diagnosis in childhood was more likely with autosomal recessive (AR)/X-linked recessive (XLR) disease or TINF2 mutations than with autosomal dominant (AD) genotypes (odds ratio [OR] 9.2; P < .01, adjusted for sex). Severe bone marrow failure developed in 111 patients (48.1%). The risk of severe bone marrow failure was higher in patients with AR/XLR disease or with TINF2 mutations (OR, 5.5) compared with those with AD disease (OR, 7.6; P < .01). In patients with AD disease, the prevalence of severe bone marrow failure was higher with TERC (56.7%) than with RTEL1 (13.8%) or TERT (25%) (P < .01).

The most common malignancies were head and neck squamous cell carcinomas (n = 11) and leukemia (n = 7). Compared with AD genotypes, the hazard ratio for any cancer was 8 for AR/XLR genotypes (95% confidence interval, 1.93-33.51, adjusted for sex and age at diagnosis). The median age of patients with myelodysplastic syndrome at diagnosis was significantly older for patients with AD genotypes (53.2 years; range, 26.6-66 years) compared with those who had AR/XLR genotypes (16.8 years, range, 5.9-47.5 years; P = .01). The median overall survival was better with AD disease (64.9 years) than with combined AR/XLR (31.8 years) and TINF2 disease (37.9 years) (P < .01), even after accounting for telomere length less than the first percentile.

This study is remarkable in the breadth and depth of the comparative analysis of different genotypes causing this rare condition. A significant subset (42%) of the cohort was systematically evaluated at the National Institutes of Health (NIH) study site, which allowed uniform in-depth evaluations per study protocol. However, this might also have introduced potential selection bias; for example, medically complex patients might have been more motivated to travel to the NIH. Importantly, the study cohort was followed longitudinally, and the analysis included consideration of patient age to assess cumulative risks over time. Many of the TBD genotypes may not manifest disease phenotypes until adulthood, and accurate diagnosis informs assessment of comorbidities and risk factors to guide management. Longitudinal cohort studies are essential to advance our understanding of these genetic bone marrow failure/cancer predisposition syndromes.

A few caveats should be considered. The majority of the analysis was driven by the most common genotypes (AD: TERT, TERC, RTEL1, TINF2; AR: DKC1, RTEL1), whereas data remain sparse for rare genotypes such as CTC1, PARN, WRAP53, ACD, and biallelic TERT. With only limited data available for rare genotypes, clinical management is extrapolated from more common TBD genotypes; however, it is possible that specific rare genotypes might carry clinical risks distinct from those of other genes within the same molecular pathway, as has been observed in Fanconi anemia.³ The effects of telomere lengths within specific tissues on clinical outcomes are not readily measurable. Telomere length is clinically assessed in granulocytes and lymphocytes⁴; however, it is possible that these might not reflect relative telomere lengths in other affected tissues such as lung or liver, which might affect organ-specific risks.

A major challenge for the clinical management of patients with these bone marrow failure and cancer predisposition conditions is the variability in clinical phenotypes and complications, even between affected members with identical TBD gene mutations from the same family. Recent studies of acquired mutations and their functional consequences in genetic bone marrow failure disorders have identified somatic mutations resulting in reversion of the germline genetic mutation, adaptive biologic compensation, or clonal progression to malignancy.^5-9 Potential additional mechanisms contributing to phenotypic variation include co-occurring modifying germline mutations, epigenetic mechanisms, and external stressors. In addition to informing risk stratification, such studies of phenotypic modifiers in the context of specific germline genetic mutations may identify potential targets for new therapies to treat these conditions. Due to space limitations, the author apologizes to all whose work could not be cited. Readers are referred to excellent recent reviews.