Abstract
Phenotypic heterogeneity is often observed in patients with telomeropathies caused by pathogenic variants in telomere biology genes. However, the roles of recessive variants in these different phenotypes are not fully characterized. Our goal is to describe the biological roles of a novel homozygous RTEL1 variant identified in a consanguineous Lebanese family with unusual presentation of telomeropathies. A proband was screened for germline variants in telomere biology genes by whole exome sequencing. Leukocytes’ telomere length was measured in the proband and eight relatives. We identified a novel homozygous p.E665K RTEL1 variant in the proband, his mother, and seven siblings that associated with telomere shortening and a broad spectrum of clinical manifestations, ranging from mild unspecific findings to severe phenotypes. Consanguinity in at least three family generations led to increased frequency of the homozygous p.E665K variant in the youngest generation and progressive telomere shortening. The increased frequency of the homozygous RTEL1 variant due to consanguinity in this Lebanese family allowed us to infer novel behaviors of recessive RTEL1 variants, as the expressivity and penetrance of this gene are very heterogenous between inter- and intra-generations. Progressive telomere shortening was associated with disease anticipation, first reported in recessive autosomal telomeropathies. Both genetic testing and telomere length measurement were critical for the clinical diagnosis of this family with telomere diseases marked by phenotypic heterogeneity.
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References
Alder JK, Hanumanthu VS, Strong MA, DeZern AE, Stanley SE, Takemoto CM, Danilova L, Applegate CD, Bolton SG, Mohr DW, Brodsky RA, Casella JF, Greider CW, Jackson JB, Armanios M (2018) Diagnostic utility of telomere length testing in a hospital-based setting. Proc Natl Acad Sci USA 115(10):E2358–E2365. https://doi.org/10.1073/pnas.1720427115
Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, Griffin CA, Eshleman JR, Cohen AR, Chakravarti A, Hamosh A, Greider CW (2005) Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci USA 102(44):15960–15964. https://doi.org/10.1073/pnas.0508124102
Ballew BJ, Joseph V, De S, Sarek G, Vannier JB, Stracker T, Schrader KA, Small TN, O’Reilly R, Manschreck C, Harlan Fleischut MM, Zhang L, Sullivan J, Stratton K, Yeager M, Jacobs K, Giri N, Alter BP, Boland J, Burdett L, Offit K, Boulton SJ, Savage SA, Petrini JH (2013) A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome. PLoS Genet 9(8):e1003695. https://doi.org/10.1371/journal.pgen.1003695
Borie R, Bouvry D, Cottin V, Gauvain C, Cazes A, Debray MP, Cadranel J, Dieude P, Degot T, Dominique S, Gamez AS, Jaillet M, Juge PA, Londono-Vallejo A, Mailleux A, Mal H, Boileau C, Menard C, Nunes H, Prevot G, Quetant S, Revy P, Traclet J, Wemeau-Stervinou L, Wislez M, Kannengiesser C, Crestani B (2019) Regulator of telomere length 1 (RTEL1) mutations are associated with heterogeneous pulmonary and extra-pulmonary phenotypes. Eur Respir J. https://doi.org/10.1183/13993003.00508-2018
Calado RT, Young NS (2009) Telomere diseases. N Engl J Med 361(24):2353–2365. https://doi.org/10.1056/NEJMra0903373
Cardoso SR, Ellison ACM, Walne AJ, Cassiman D, Raghavan M, Kishore B, Ancliff P, Rodríguez-Vigil C, Dobbels B, Rio-Machin A, Al Seraihi AFH, Pontikos N, Tummala H, Vulliamy T, Dokal I (2017) Myelodysplasia and liver disease extend the spectrum of RTEL1 related telomeropathies. Haematologica 102(8):e293–e296. https://doi.org/10.3324/haematol.2017.167056
Cogan JD, Kropski JA, Zhao M, Mitchell DB, Rives L, Markin C, Garnett ET, Montgomery KH, Mason WR, McKean DF, Powers J, Murphy E, Olson LM, Choi L, Cheng DS, Blue EM, Young LR, Lancaster LH, Steele MP, Brown KK, Schwarz MI, Fingerlin TE, Schwartz DA, Lawson WE, Loyd JE, Zhao Z, Phillips JA, Blackwell TS (2015) Rare variants in RTEL1 are associated with familial interstitial pneumonia. Am J Respir Crit Care Med 191(6):646–655. https://doi.org/10.1164/rccm.201408-1510OC
Desvignes JP, Bartoli M, Delague V, Krahn M, Miltgen M, Béroud C, Salgado D (2018) VarAFT: a variant annotation and filtration system for human next generation sequencing data. Nucleic Acids Res 46(W1):W545–W553. https://doi.org/10.1093/nar/gky471
Ding H, Schertzer M, Wu X, Gertsenstein M, Selig S, Kammori M, Pourvali R, Poon S, Vulto I, Chavez E, Tam PP, Nagy A, Lansdorp PM (2004) Regulation of murine telomere length by Rtel: an essential gene encoding a helicase-like protein. Cell 117(7):873–886. https://doi.org/10.1016/j.cell.2004.05.026
Gutierrez-Rodrigues F, Santana-Lemos BA, Scheucher PS, Alves-Paiva RM, Calado RT (2014) Direct comparison of flow-FISH and qPCR as diagnostic tests for telomere length measurement in humans. PLoS One 9(11):e113747. https://doi.org/10.1371/journal.pone.0113747
Gutierrez-Rodrigues F, Donaires FS, Pinto A, Vicente A, Dillon LW, Clé DV, Santana BA, Pirooznia M, Ibanez MDPF, Townsley DM, Kajigaya S, Hourigan CS, Cooper JN, Calado RT, Young NS (2019) Pathogenic TERT promoter variants in telomere diseases. Genet Med 21(7):1594–1602. https://doi.org/10.1038/s41436-018-0385-x
Hamamy H, Antonarakis SE, Cavalli-Sforza LL, Temtamy S, Romeo G, Kate LP, Bennett RL, Shaw A, Megarbane A, van Duijn C, Bathija H, Fokstuen S, Engel E, Zlotogora J, Dermitzakis E, Bottani A, Dahoun S, Morris MA, Arsenault S, Aglan MS, Ajaz M, Alkalamchi A, Alnaqeb D, Alwasiyah MK, Anwer N, Awwad R, Bonnefin M, Corry P, Gwanmesia L, Karbani GA, Mostafavi M, Pippucci T, Ranza-Boscardin E, Reversade B, Sharif SM, Teeuw ME, Bittles AH (2011) Consanguineous marriages, pearls and perils: geneva International Consanguinity Workshop Report. Genet Med 13(9):841–847. https://doi.org/10.1097/GIM.0b013e318217477f
Kannengiesser C, Borie R, Ménard C, Réocreux M, Nitschké P, Gazal S, Mal H, Taillé C, Cadranel J, Nunes H, Valeyre D, Cordier JF, Callebaut I, Boileau C, Cottin V, Grandchamp B, Revy P, Crestani B (2015) Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis. Eur Respir J 46(2):474–485. https://doi.org/10.1183/09031936.00040115
Khincha PP, Wentzensen IM, Giri N, Alter BP, Savage SA (2014) Response to androgen therapy in patients with dyskeratosis congenita. Br J Haematol 165(3):349–357. https://doi.org/10.1111/bjh.12748
Khincha PP, Bertuch AA, Gadalla SM, Giri N, Alter BP, Savage SA (2018) Similar telomere attrition rates in androgen-treated and untreated patients with dyskeratosis congenita. Blood Adv 2(11):1243–1249. https://doi.org/10.1182/bloodadvances.2018016964
Kirschner M, Ventura Ferreira M, Bouillon A, Wlodarski M, Schwarz M, Balabanov S, Wilop S, Koschmieder S, Panse J, Brümmendorf T, Beier F (2018) Androgen derivatives improve blood counts and elongate telomere length in patients with dyskeratosis congenita. Abstracts and Meeting Program: Blood
Le Guen T, Jullien L, Touzot F, Schertzer M, Gaillard L, Perderiset M, Carpentier W, Nitschke P, Picard C, Couillault G, Soulier J, Fischer A, Callebaut I, Jabado N, Londono-Vallejo A, de Villartay JP, Revy P (2013) Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability. Hum Mol Genet 22(16):3239–3249. https://doi.org/10.1093/hmg/ddt178
Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25(14):1754–1760. https://doi.org/10.1093/bioinformatics/btp324
Marsh JCW, Gutierrez-Rodrigues F, Cooper J, Jiang J, Gandhi S, Kajigaya S, Feng X, Ibanez MDPF, Donaires FS, Lopes da Silva JP, Li Z, Das S, Ibanez M, Smith AE, Lea N, Best S, Ireland R, Kulasekararaj AG, McLornan DP, Pagliuca A, Callebaut I, Young NS, Calado RT, Townsley DM, Mufti GJ (2018) Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms. Blood Adv 2(1):36–48. https://doi.org/10.1182/bloodadvances.2017008110
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20(9):1297–1303. https://doi.org/10.1101/gr.107524.110
Niewisch MR, Savage SA (2019) An update on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol. https://doi.org/10.1080/17474086.2019.1662720
Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M, Topper S, Invitae Clinical Genomics Group (2017) Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med 19(10):1105–1117. https://doi.org/10.1038/gim.2017.37
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424. https://doi.org/10.1038/gim.2015.30
Speckmann C, Sahoo SS, Rizzi M, Hirabayashi S, Karow A, Serwas NK, Hoemberg M, Damatova N, Schindler D, Vannier JB, Boulton SJ, Pannicke U, Göhring G, Thomay K, Verdu-Amoros JJ, Hauch H, Woessmann W, Escherich G, Laack E, Rindle L, Seidl M, Rensing-Ehl A, Lausch E, Jandrasits C, Strahm B, Schwarz K, Ehl SR, Niemeyer C, Boztug K, Wlodarski MW (2017) Clinical and molecular heterogeneity of RTEL1 deficiency. Front Immunol 8:449. https://doi.org/10.3389/fimmu.2017.00449
Touzot F, Kermasson Laetitia (2016) Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations. Blood Adv 1(1):36–46
Townsley DM, Dumitriu B, Young NS (2014) Bone marrow failure and the telomeropathies. Blood 124(18):2775–2783. https://doi.org/10.1182/blood-2014-05-526285
Townsley Danielle M, Dumitriu Bogdan, Liu Delong, Biancotto Angélique, Weinstein Barbara, Chen Christina, Hardy Nathan, Mihalek Andrew D, Lingala Shilpa, Kim Yun Ju, Yao Jianhua, Jones Elizabeth, Gochuico Bernadette R, Heller Theo, Wu Colin O, Calado Rodrigo T, Scheinberg Phillip, Young Neal S (2016) Danazol treatment for telomere diseases. N Engl J Med 375(11):1095–1096. https://doi.org/10.1056/NEJMc1607752
Vannier JB, Sarek G, Boulton SJ (2014) RTEL1: functions of a disease-associated helicase. Trends Cell Biol 24(7):416–425. https://doi.org/10.1016/j.tcb.2014.01.004
Vulliamy T, Marrone A, Szydlo R, Walne A, Mason PJ, Dokal I (2004) Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat Genet 36(5):447–449. https://doi.org/10.1038/ng1346
Walne AJ, Vulliamy T, Kirwan M, Plagnol V, Dokal I (2013) Constitutional mutations in RTEL1 cause severe dyskeratosis congenita. Am J Hum Genet 92(3):448–453. https://doi.org/10.1016/j.ajhg.2013.02.001
Ziegler P, Schrezenmeier H, Akkad J, Brassat U, Vankann L, Panse J, Wilop S, Balabanov S, Schwarz K, Martens UM, Brümmendorf TH (2012) Telomere elongation and clinical response to androgen treatment in a patient with aplastic anemia and a heterozygous hTERT gene mutation. Ann Hematol 91(7):1115–1120. https://doi.org/10.1007/s00277-012-1454-x
Acknowledgements
This work was funded by the Intramural Research Program of the National Heart, Lung, and Blood Institute/NIH, and by grants from Saint Joseph University, Beirut, Lebanon and the São Paulo Research Foundation/CAPES (FAPESP; Grant Number, 13/08135-2). We would like to thank the Bioinformatics and Computational Core Facility at the NHLBI for data analysis.
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Contribution: FGR, NM, EC, and HF wrote the article, performed experimental assays and collected clinical data. AV and CD contributed to experimental assays and data analysis; EC and NJ contributed for sequencing bioinformatics data analysis and study design; NM, FA, WS, NB, HF, and MLC contributed to patients’ recruitment and data analysis; RTC contributed to telomere length measurement analysis; NSY, HF, and MLC contributed to study design, data interpretation and both had full access to all the data in this study and had final responsibility for the decision to submit for publication. FGR, NM, EC, CD, SK, RTC, NSY, HF, and MLC critically reviewed the manuscript for intellectual content.
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Gutierrez-Rodrigues, F., Masri, N., Chouery, E. et al. A novel homozygous RTEL1 variant in a consanguineous Lebanese family: phenotypic heterogeneity and disease anticipation. Hum Genet 138, 1323–1330 (2019). https://doi.org/10.1007/s00439-019-02076-8
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DOI: https://doi.org/10.1007/s00439-019-02076-8