An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis

Petrovski, Slavé; Todd, Jamie L.; Durheim, Michael T.; Wang, Quanli; Chien, Jason W.; Kelly, Francine L.; Frankel, Courtney W.; Mebane, Caroline; Ren, Zhong; Bridgers, Joshua; Urban, Thomas; Malone, Colin D.; Copeland, Ashley Finlen; Brinkley, Christie; Allen, Andrew S.; O’Riordan, Thomas G.; McHutchison, John G.; Palmer, Scott M.; Goldstein, David B.

doi:10.1164/rccm.201610-2088oc

Cited by 195 publications

(202 citation statements)

References 37 publications

(52 reference statements)

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“…Heterozygous LoF mutations in PARN have recently been implicated in late-onset idiopathic pulmonary fibrosis; myelodysplastic syndrome; and, rarely, liver fibrosis. However, to our knowledge they have yet to be associated with kidney disease (28, 39, 40). The PARN mutations detected in the patients with CKD were absent in all public databases.…”

Section: Resultsmentioning

confidence: 97%

“…Recessive mutations in PARN cause dyskeratosis congenita (44), a rare multisystem disorder presenting as severe bone marrow failure and abnormal cancer, skin, and mucosal pathology; many other organs, including the kidney, can also be affected (45). PARN haploinsufficiency produces variably penetrant pulmonary, bone marrow, and liver fibrosis in older adults, but the reason for interindividual differences in affected organs is unknown (28, 40, 46). The finding of 2 independent LoF mutations in 3 patients with nephropathy extends the phenotypes associated with PARN mutations and identifies renal tubulointerstitial fibrosis as another potential consequence of PARN haploinsufficiency, suggesting new avenues for investigating mechanisms of kidney injury.…”

Section: Discussionmentioning

confidence: 99%

“…Recent investigations indicate that many late-onset constitutional disorders, such as amyotrophic lateral sclerosis (48) and pulmonary fibrosis (28, 40), also have a strong genetic basis that can be identified using these technologies. Our study similarly suggests that WES can provide a specific, molecular-level diagnosis, supporting its utility as part of the clinical diagnostic work-up.…”

Section: Discussionmentioning

confidence: 99%

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Whole-Exome Sequencing in Adults With Chronic Kidney Disease

et al. 2017

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Background The utility of whole-exome sequencing (WES) for the diagnosis and management of adult-onset constitutional disorders has not been adequately studied. Genetic diagnostics may be advantageous in adults with chronic kidney disease (CKD), in whom the cause of kidney failure often remains unknown. Objective To study the diagnostic utility of WES in a selected referral population of adults with CKD. Design Observational cohort. Setting A major academic medical center. Patients 92 adults with CKD of unknown cause or familial nephropathy or hypertension. Measurements The diagnostic yield of WES and its potential effect on clinical management. Results Whole-exome sequencing provided a diagnosis in 22 of 92 patients (24%), including 9 probands with CKD of unknown cause and encompassing 13 distinct genetic disorders. Among these, loss-of-function mutations were identified in PARN in 2 probands diagnosed respectively with tubulointerstitial fibrosis and CKD of unknown cause. PARN mutations have been implicated in a short telomere syndrome characterized by lung, bone marrow, and liver fibrosis; these findings extend the phenotype of PARN mutations to renal fibrosis. In addition, review of the American College of Medical Genetics actionable genes identified a pathogenic BRCA2 mutation in a proband who was diagnosed with breast cancer on follow-up. The results affected clinical management in most identified cases, including initiation of targeted surveillance, familial screening to guide donor selection for transplantation, and changes in therapy. Limitation The small sample size and recruitment at a tertiary care academic center limit generalizability of findings among the broader CKD population. Conclusion Whole-exome sequencing identified diagnostic mutations in a substantial number of adults with CKD of many causes. Further study of the utility of WES in the evaluation and care of patients with CKD in additional settings is warranted. Primary Funding Source New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health.

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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Whole-Exome Sequencing in Adults With Chronic Kidney Disease

et al. 2017

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“…Furthermore, 25-30% of patients with sporadic IPF have substantially shorter telomeres in both leukocytes and AEC2s 38 . Moreover, a recent casecontrol, exome-wide collapsing analysis identified variants in TERT, RTEL1 and PARN as significant contributors to sporadic IPF 39 .…”

Section: Sporadic Ipfmentioning

confidence: 99%

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora

Rojas

Pardo

et al. 2017

Nat Rev Drug Discov

290

212

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Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches.Fibrosis as a pathogenic mechanism occurs in numerous organs and diseases. Fibrosis results from abnormal tissue repair and is associated with persistent and/or severe tissue damage and cellular stress. Epithelial and/or endothelial injury caused by various insults triggers interrelated wound-healing pathways to restore homeostasis 1 . Failure to adequately contain or eliminate inciting factors can exacerbate inflammation and chronic woundCorrespondence to A.L.M. anamora@pitt.edu. Competing interests statementThe authors declare competing interests: see Web version for details. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript healing responses, resulting in continued tissue damage and inadequate regeneration and, ultimately, fibrosis 2 . Although their aetiology and causative mechanisms differ, the various fibrotic diseases all have abnormal and exaggerated accumulation of extracellular matrix (ECM) components, mainly fibrillar collagens. The resulting fibrosis disturbs the normal architecture of affected organs, which ultimately leads to their dysfunction and failure. Nearly 45% of deaths in the developed world are attributable to some type of chronic fibroproliferative disease, including idiopathic pulmonary fibrosis (IPF) and end-stage fibrotic liver, kidney and heart disease 2 . The progressive nature of these diseases and the absence of effective treatments mean that a better understanding of the cellular and molecular mechanisms that contribute to the development of fibrosis is needed.Although IPF was originally thought to be an inflammation-driven disorder, clinical trials with a combination of anti-inflammatory drugs (prednisone, azathioprine and N-acetyl-Lcysteine (NAC)), failed to improve outcomes and instead increased mortality 3 . In 2014, two drugs, pirfenidone, a drug with poorly understood mechanisms, and nintedanib, a tyrosine kinase inhibitor, were approved for the treatment of IPF ...

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“…Furthermore, 25–30% of patients with sporadic IPF have substantially shorter telomeres in both leukocytes and AEC2s 38 . Moreover, a recent case–control, exome-wide collapsing analysis identified variants in TERT, RTEL1 and PARN as significant contributors to sporadic IPF 39 .…”

Section: Genetic Susceptibilitymentioning

confidence: 99%

Erratum: Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora¹,

Rojas²,

Pardo³

et al. 2017

Nat Rev Drug Discov

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An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis

Abstract: We identified TERT, RTEL1, and PARN-three telomere-related genes previously implicated in familial pulmonary fibrosis-as significant contributors to sporadic IPF. These results support the idea that telomere dysfunction is involved in IPF pathogenesis.

Cited by 195 publications

References 37 publications

Whole-Exome Sequencing in Adults With Chronic Kidney Disease

Whole-Exome Sequencing in Adults With Chronic Kidney Disease

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Erratum: Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

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