Severe hematologic complications after lung transplantation in patients with telomerase complex mutations

Borie, Raphaël; Kannengiesser, Caroline; Hirschi, Sandrine; Pavec, Jérôme Le; Mal, Hervé; Bergot, Emmanuel; Jouneau, S.; Naccache, Jean‐Marc; Revy, Patrick; Boutboul, David; Tour, Régis Peffault de la; Wémeau-Stervinou, Lidwine; Philit, F.; Cordier, Jean-François; Thabut, Gabriel; Crestani, Bruno; Cottin, Vincent

doi:10.1016/j.healun.2014.11.010

Cited by 112 publications

(100 citation statements)

References 32 publications

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“…Thrombocytopenia and a need for platelet transfusion were frequent, and myelodysplastic syndrome and/or bone-marrow failure occurred in some patients. Acute kidney failure requiring dialysis support seemed unexpectedly frequent in two series (0-50%) [58][59][60]. The prevalence of infections and acute/chronic rejections did not differ from historical data, but there was no control group.…”

Section: Pulmonary Involvementmentioning

confidence: 79%

“…Three retrospective series recently reported the outcome of lung transplantation in 26 patients with TERT and TERC mutations [58][59][60]. Almost all patients required adjustment of immunosuppression because of haematological toxicity.…”

Section: Pulmonary Involvementmentioning

confidence: 99%

“…Indeed, carriers of telomerase complex mutations show a high rate of haematological complications after lung transplantation [58,59] and a close evaluation of those patients is mandatory before inclusion on the transplant list, particularly when there is TERT, RTEL1, TERC, PARN, DKC1 or TINF2 mutation and thrombocytopenia <80 000 platelets·mm −3 , or myelodysplastic syndrome, or somatic cytogenic abnormalities with poor prognosis.In those patients, immunosuppressive drugs are more closely monitored and tapered, and azathioprine and mycophenolate mofetil are avoided as much as possible.…”

Section: Indication For Genetic Diagnosismentioning

confidence: 99%

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Management of suspected monogenic lung fibrosis in a specialised centre

et al. 2017

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At least 10% of patients with interstitial lung disease present monogenic lung fibrosis suspected on familial aggregation of pulmonary fibrosis, specific syndromes or early age of diagnosis. Approximately 25% of families have an identified mutation in genes mostly involved in telomere homeostasis, and more rarely in surfactant homeostasis.Beyond pathophysiological knowledge, detection of these mutations has practical consequence for patients. For instance, mutations involved in telomere homeostasis are associated with haematological complications after lung transplantation and may require adapted immunosuppression. Moreover, relatives may benefit from a clinical and genetic evaluation that should be specifically managed.The field of genetics of pulmonary fibrosis has made great progress in the last 10 years, raising specific problems that should be addressed by a specialised team.

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Section: Pulmonary Involvementmentioning

confidence: 79%

Section: Pulmonary Involvementmentioning

confidence: 99%

Section: Indication For Genetic Diagnosismentioning

confidence: 99%

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Management of suspected monogenic lung fibrosis in a specialised centre

et al. 2017

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“…In an international series of patients with IPF who underwent lung transplantation, carriers of loss-of-function telomerase mutations were shown to be at high risk of severe post-transplant complications, particularly bone marrow failure, reflecting the syndromic nature of their disease 111. These observations, coupled with those of a recent study from the French GERM‘O’P,112 indicate that, similar to bone marrow recipients, genetic screening for telomere syndromes may inform haematological risk and guide post-transplant management in patients with IPF 113…”

Section: Potential Implications Of Genetic Discoveriesmentioning

confidence: 83%

Genetics of idiopathic pulmonary fibrosis: from mechanistic pathways to personalised medicine

Spagnolo

Cottin

2016

J Med Genet

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Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and ultimately fatal disorder for which there is no cure. While the disease is by definition idiopathic, accumulating evidence, including familial aggregation of cases and the occurrence of pulmonary fibrosis in the context of a number of rare genetic disorders, indicates that genetic factors contribute significantly to the pathogenesis of IPF. Several disease-associated genetic variants, both rare and common, have been identified in familial and sporadic IPF. While the full clinical implications of these genetic associations remain to be elucidated, observational studies suggest that genotype influences the development of the disease and its outcome. Available data indicate that genetics has the potential to identify individuals at risk of IPF, classify patients more precisely, clarify the key pathways involved in disease pathogenesis and eventually develop more effective targeted therapies. Considerable research is required before a comprehensive disease fingerprint of IPF can be delivered. Nevertheless, the application of rapidly evolving molecular biology and genomic technologies combined with appropriate bioinformatic methodology offers an unprecedented and realistic opportunity to achieve this goal.

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“…These data suggest that some drugs, and particularly alkylating agents, should be used with caution in patients with RTEL1 mutations. Myelodysplasia secondary to immunosuppressants was recently reported in patients with TERT or TERC mutations [54,55].…”

Section: Discussionmentioning

confidence: 99%

HeterozygousRTEL1mutations are associated with familial pulmonary fibrosis

et al. 2015

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Pulmonary fibrosis is a fatal disease with progressive loss of respiratory function. Defective telomere maintenance leading to telomere shortening is a cause of pulmonary fibrosis, as mutations in the telomerase component genes TERT (reverse transcriptase) and TERC (RNA component) are found in 15% of familial pulmonary fibrosis (FPF) cases. However, so far, about 85% of FPF remain genetically uncharacterised.Here, in order to identify new genetic causes of FPF, we performed whole-exome sequencing, with a candidate-gene approach, of 47 affected subjects from 35 families with FPF without TERT and TERC mutations.We identified heterozygous mutations in regulator of telomere elongation helicase 1 (RTEL1) in four families. RTEL1 is a DNA helicase with roles in DNA replication, genome stability, DNA repair and telomere maintenance. The heterozygous RTEL1 mutations segregated as an autosomal dominant trait in FPF, and were predicted by structural analyses to severely affect the function and/or stability of RTEL1. In agreement with this, RTEL1-mutated patients exhibited short telomeres in comparison with age-matched controls.Our results provide evidence that heterozygous RTEL1 mutations are responsible for FPF and, thereby, extend the clinical spectrum of RTEL1 deficiency. Thus, RTEL1 enlarges the number of telomereassociated genes implicated in FPF. @ERSpublications Whole-exome sequencing reveals heterozygous RTEL1 mutations in familial pulmonary fibrosis with short telomeres

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Severe hematologic complications after lung transplantation in patients with telomerase complex mutations

Abstract: Background: Mutations in the telomerase complex (TERT and TR) are associated with

Cited by 112 publications

References 32 publications

Management of suspected monogenic lung fibrosis in a specialised centre

Management of suspected monogenic lung fibrosis in a specialised centre

Genetics of idiopathic pulmonary fibrosis: from mechanistic pathways to personalised medicine

HeterozygousRTEL1mutations are associated with familial pulmonary fibrosis

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