The evolving genetic landscape of telomere biology disorder dyskeratosis congenita

Hemanth Tummala; Amanda J. Walne; Mohsin Badat; Manthan Patel; Abigail M. Walne; Jenna Alnajar; Chi Ching Chow; Ibtehal Albursan; Jennifer M. Frost; David Ballard; Sally Killick; Peter Szitányi; Anne M. Kelly; Manoj Raghavan; Corrina Powell; Reinier Raymakers; Tony Todd; Elpis Mantadakis; Sophia Polychronopoulou; Nikolas Pontikos; Tianyi Liao; Pradeep Madapura; Upal Hossain; Tom Vulliamy; Inderjeet Dokal

doi:10.1038/s44321-024-00118-x

The evolving genetic landscape of telomere biology disorder dyskeratosis congenita

Hemanth Tummala^*, Amanda J. Walne, Mohsin Badat, Manthan Patel, Abigail M. Walne, Jenna Alnajar, Chi Ching Chow, Ibtehal Albursan, Jennifer M. Frost, David Ballard, Sally Killick, Peter Szitányi, Anne M. Kelly, Manoj Raghavan, Corrina Powell, Reinier Raymakers, Tony Todd, Elpis Mantadakis, Sophia Polychronopoulou, Nikolas PontikosTianyi Liao, Pradeep Madapura, Upal Hossain, Tom Vulliamy, Inderjeet Dokal

^*Corresponding author for this work

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Abstract

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as ‘DC-like’ (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients’ blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.

Original language	English
Pages (from-to)	2560-2582
Number of pages	23
Journal	Embo Molecular Medicine
Volume	16
Issue number	10
Early online date	28 Aug 2024
DOIs	https://doi.org/10.1038/s44321-024-00118-x
Publication status	Published - 14 Oct 2024

Keywords

Dyskeratosis Congenita
ncRNAs
POLA1
Telomeres

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Tummala, H., Walne, A. J., Badat, M., Patel, M., Walne, A. M., Alnajar, J., Chow, C. C., Albursan, I., Frost, J. M., Ballard, D., Killick, S., Szitányi, P., Kelly, A. M., Raghavan, M., Powell, C., Raymakers, R., Todd, T., Mantadakis, E., Polychronopoulou, S., ... Dokal, I. (2024). The evolving genetic landscape of telomere biology disorder dyskeratosis congenita. Embo Molecular Medicine, 16(10), 2560-2582. https://doi.org/10.1038/s44321-024-00118-x

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title = "The evolving genetic landscape of telomere biology disorder dyskeratosis congenita",

abstract = "Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as {\textquoteleft}DC-like{\textquoteright} (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients{\textquoteright} blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.",

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author = "Hemanth Tummala and Walne, {Amanda J.} and Mohsin Badat and Manthan Patel and Walne, {Abigail M.} and Jenna Alnajar and Chow, {Chi Ching} and Ibtehal Albursan and Frost, {Jennifer M.} and David Ballard and Sally Killick and Peter Szit{\'a}nyi and Kelly, {Anne M.} and Manoj Raghavan and Corrina Powell and Reinier Raymakers and Tony Todd and Elpis Mantadakis and Sophia Polychronopoulou and Nikolas Pontikos and Tianyi Liao and Pradeep Madapura and Upal Hossain and Tom Vulliamy and Inderjeet Dokal",

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Tummala, H, Walne, AJ, Badat, M, Patel, M, Walne, AM, Alnajar, J, Chow, CC, Albursan, I, Frost, JM, Ballard, D, Killick, S, Szitányi, P, Kelly, AM, Raghavan, M, Powell, C, Raymakers, R, Todd, T, Mantadakis, E, Polychronopoulou, S, Pontikos, N, Liao, T, Madapura, P, Hossain, U, Vulliamy, T & Dokal, I 2024, 'The evolving genetic landscape of telomere biology disorder dyskeratosis congenita', Embo Molecular Medicine, vol. 16, no. 10, pp. 2560-2582. https://doi.org/10.1038/s44321-024-00118-x

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T1 - The evolving genetic landscape of telomere biology disorder dyskeratosis congenita

AU - Tummala, Hemanth

AU - Walne, Amanda J.

AU - Badat, Mohsin

AU - Patel, Manthan

AU - Walne, Abigail M.

AU - Alnajar, Jenna

AU - Chow, Chi Ching

AU - Albursan, Ibtehal

AU - Frost, Jennifer M.

AU - Ballard, David

AU - Killick, Sally

AU - Szitányi, Peter

AU - Kelly, Anne M.

AU - Raghavan, Manoj

AU - Powell, Corrina

AU - Raymakers, Reinier

AU - Todd, Tony

AU - Mantadakis, Elpis

AU - Polychronopoulou, Sophia

AU - Pontikos, Nikolas

AU - Liao, Tianyi

AU - Madapura, Pradeep

AU - Hossain, Upal

AU - Vulliamy, Tom

AU - Dokal, Inderjeet

PY - 2024/10/14

Y1 - 2024/10/14

N2 - Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as ‘DC-like’ (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients’ blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.

AB - Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as ‘DC-like’ (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients’ blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.

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KW - ncRNAs

KW - POLA1

KW - Telomeres

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DO - 10.1038/s44321-024-00118-x

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SP - 2560

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ER -

The evolving genetic landscape of telomere biology disorder dyskeratosis congenita

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