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Genetics of human telomere biology disorders

Nature Reviews Genetics volume 24, pages 86–108 (2023)Cite this article

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Abstract

Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that prevent the activation of DNA damage response and repair pathways. Numerous factors localize at telomeres to regulate their length, structure and function, to avert replicative senescence or genome instability and cell death. In humans, Mendelian defects in several of these factors can result in abnormally short or dysfunctional telomeres, causing a group of rare heterogeneous premature-ageing diseases, termed telomeropathies, short-telomere syndromes or telomere biology disorders (TBDs). Here, we review the TBD-causing genes identified so far and describe their main functions associated with telomere biology. We present molecular aspects of TBDs, including genetic anticipation, phenocopy, incomplete penetrance and somatic genetic rescue, which underlie the complexity of these diseases. We also discuss the implications of phenotypic and genetic features of TBDs on fundamental aspects related to human telomere biology, ageing and cancer, as well as on diagnostic, therapeutic and clinical approaches.

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Fig. 1: Causes and consequences of telomere dysfunction in normal ageing and telomere biology disorders.
Fig. 2: Factors associated with telomere biology disorders.
Fig. 3: Specific genotype–phenotype features in TBDs.
Fig. 4: Mechanisms of somatic genetic rescue in telomere biology disorders.

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Acknowledgements

The authors apologize to colleagues whose work could not be cited owing to restriction in the number of references allowed. P.R. thanks the members of the GDIS lab and is grateful to A. Fischer for discussion, advice and constant support. P.R. also thanks A. Decottignies and A. Fischer for critical reading of the manuscript. Current work in P.R.’s laboratory is funded by INSERM, Ligue Nationale contre le cancer, INCa and ANR. P.R. is a scientist from Centre National de la Recherche Scientifique (CNRS). Current work in A.A.B.’s laboratory is funded by the National Cancer Institute.

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Authors and Affiliations

  1. INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue Nationale contre le Cancer, Paris, France

    Patrick Revy

  2. Université Paris Cité, Imagine Institute, Paris, France

    Patrick Revy

  3. APHP Service de Génétique, Hôpital Bichat, Paris, France

    Caroline Kannengiesser

  4. Inserm U1152, Université Paris Cité, Paris, France

    Caroline Kannengiesser

  5. Departments of Paediatrics and Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Alison A. Bertuch

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P.R. and A.A.B. wrote the article. All authors contributed equally to all other aspects of the article.

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Glossary

R-loops

Nucleic acid structures composed of an RNA–DNA hybrid and a displaced single-stranded DNA that accumulate at specific regions genome-wide, including telomeres. R-loops can cause replication stress and genome instability.

G-quadruplexes

Four DNA stranded secondary structures formed in G-rich sequences in which four guanines form a planar array via Hoogsteen base-pairing. These structures can cause replication stress.

Somatic genetic rescue

In Mendelian disorders, an in vivo somatic genetic event that partially or totally counteracts the deleterious effect of the pathogenic germline mutation and provides a selective advantage over non-somatically modified cells.

Clones

Cells that originate from a common cell ancestor (progenitor) with identical genetic identity.

Genetic anticipation

A phenomenon observed in autosomal dominant diseases in which some clinical manifestations develop earlier and are more severe with successive generations.

Phenocopy

A phenomenon whereby the phenotype dissociates from the genotype. In the present Review, when individuals with familial telomere biology disease exhibit short telomeres and/or premature ageing without carrying the causative germline variant.

Repeat addition processivity

(RAP). The ability of telomerase to synthesize multiple telomeric repeats without dissociating from the telomere.

Monoallelic

Refers to one genetic variant located on one allele of a gene.

Biallelic

Refers to two (possibly different) variants located on both alleles of the same gene.

Hypomorphic

Refers to a variant that results in reduced but not eliminated function of the gene product.

Compound heterozygous

The existence of distinct mutations on opposite alleles of a single gene located on an autosomal chromosome.

Cajal bodies

Distinct sub-nuclear structures present in eukaryotic cells associated with RNA metabolism and ribonucleoprotein biogenesis.

Incomplete penetrance

Refers to the phenomenon of some individuals who carry a pathogenic variant who do not exhibit clinical signs.

Variable expressivity

Refers to the phenomenon of individuals affected by a Mendelian disease who exhibit different clinical features.

t-circles

Extrachromosomal circular DNA molecules that contain telomeric repeat sequences.

Uniparental isodisomy

Refers to both copies of a chromosome originating from one parent (maternal or paternal) and the chromosome from the other parent being absent. Segmental uniparental isodisomy occurs when only part of a chromosome is affected.

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Revy, P., Kannengiesser, C. & Bertuch, A.A. Genetics of human telomere biology disorders. Nat Rev Genet 24, 86–108 (2023). https://doi.org/10.1038/s41576-022-00527-z

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