COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA

Background: Rare missense mutations in the gene encoding coatomer subunit alpha (COPA) have recently been shown to cause autoimmune interstitial lung, joint and kidney disease, also known as COPA syndrome, under a dominant mode of inheritance. Case presentation: Here we describe an Icelandic family with three affected individuals over two generations with a rare clinical presentation of lung and joint disease and a histological diagnosis of follicular bronchiolitis. We performed whole-genome sequencing (WGS) of the three affected as well as three unaffected members of the family, and searched for rare genotypes associated with disease using 30,067 sequenced Icelanders as a reference population. We assessed all coding and splicing variants, prioritizing variants in genes known to cause interstitial lung disease. We detected a heterozygous missense mutation, p.Glu241Lys, in the COPA gene, private to the affected family members. The mutation occurred de novo in the paternal germline of the index case and was absent from 30,067 Icelandic genomes and 141,353 individuals from the genome Aggregation Database (gnomAD). The mutation occurs within the conserved and functionally important WD40 domain of the COPA protein. Conclusions: This is the second report of the p.Glu241Lys mutation in COPA, indicating the recurrent nature of the mutation. The mutation was reported to co-segregate with COPA syndrome in a large family from the USA with five affected members, and classified as pathogenic. The two separate occurrences of the p.Glu241Lys mutation in cases and its absence from a large number of sequenced genomes confirms its role in the pathogenesis of the COPA syndrome. Keywords: COPA syndrome, Lung disease, Arthritis, Immune dysregulation, Case reportPeer Reviewe

COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesBackground: Rare missense mutations in the gene encoding coatomer subunit alpha (COPA) have recently been shown to cause autoimmune interstitial lung, joint and kidney disease, also known as COPA syndrome, under a dominant mode of inheritance. Case presentation: Here we describe an Icelandic family with three affected individuals over two generations with a rare clinical presentation of lung and joint disease and a histological diagnosis of follicular bronchiolitis. We performed whole-genome sequencing (WGS) of the three affected as well as three unaffected members of the family, and searched for rare genotypes associated with disease using 30,067 sequenced Icelanders as a reference population. We assessed all coding and splicing variants, prioritizing variants in genes known to cause interstitial lung disease. We detected a heterozygous missense mutation, p.Glu241Lys, in the COPA gene, private to the affected family members. The mutation occurred de novo in the paternal germline of the index case and was absent from 30,067 Icelandic genomes and 141,353 individuals from the genome Aggregation Database (gnomAD). The mutation occurs within the conserved and functionally important WD40 domain of the COPA protein. Conclusions: This is the second report of the p.Glu241Lys mutation in COPA, indicating the recurrent nature of the mutation. The mutation was reported to co-segregate with COPA syndrome in a large family from the USA with five affected members, and classified as pathogenic. The two separate occurrences of the p.Glu241Lys mutation in cases and its absence from a large number of sequenced genomes confirms its role in the pathogenesis of the COPA syndrome

Fast diagnostic track for suspected lung cancer: A patient centered approach

Efst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinnInngangur: Markmið rannsóknarinnar var að lýsa einkennum, sjúkdómsmynd, meðferð og afdrifum sjúklinga sem hafa farið í kerfisbundið greiningarferli á Landspítala vegna gruns um lungnakrabbamein. Efniviður og aðferðir: Rannsóknin tekur til 550 sjúklinga (meðalaldur 68,1 ár, 57% konur) sem fóru í greiningarferlið með sólarhringslangri innlögn, frá 1. febrúar 2008 til 31. janúar 2015. Úr sjúkraskrám var aflað upplýsinga um sérkenni sjúklinga, greiningarrannsóknir, sjúkdómsgreiningu, meðferð og tímasetningu þessara þátta. Einnig var sjúkdómsmynd og lifun sjúklinga sem greindust með lungnakrabbamein á Íslandi árið 2014 (n=167, meðalaldur 69,3 ár, 61,7% konur) borin saman með fjölbreytugreiningu eftir því hvort greining var gerð innan eða utan greiningarferlis. Niðurstöður: Af 550 sjúklingum sem fóru gegnum greiningarferlið greindust 426 með lungnakrabbamein (77,5%) og voru 346 (81,2%) þeirra af öðrum vefjagerðum en smáfrumukrabbameini (NSCLC). Hlutfall sjúklinga á Íslandi sem greindust með lungnakrabbamein í greiningarferlinu jókst úr 23,3% árið 2008 í 47,9% árið 2014 (p<0,001). Tímalengd frá tilvísun að greiningu lungnakrabbameins var að miðgildi 10 dagar og 19 dagar frá greiningu til upphafs meðferðar. Sjúklingar í greiningarferli voru sjaldnar með útbreitt mein en sjúklingar utan þess, 37,5% borið saman við 70,1% (p<0,05). Þegar leiðrétt var fyrir aldri, kyni, vefjaflokki, stigun við greiningu og meðferð voru sjúklingar utan greiningarferlis með lakari lifun en sjúklingar sem greindust innan greiningarferlis, en munurinn var ekki tölfræðilega marktækur (áhættuhlutfall: 1,60; 95% öryggisbil: 0,95-2,71). Ályktun: Allt að helmingur lungnakrabbameinsgreininga á Íslandi er nú gerður í kerfisbundnu greiningarferli á Landspítala með hugsanlegum ávinningi fyrir heilsu sjúklinga. Biðtími að greiningu og meðferð hér á landi er í samræmi við alþjóðlegar ráðleggingar. Introduction: The aim of this study is to describe the characteristics of patients who underwent a fast diagnostic track (FDT) due to suspected lung cancer at Landspitali University Hospital, Iceland. Material and methods: Hospital records were reviewed on background characteristics, diagnosis, staging, waiting times and survival of all 550 patients (mean age 68.1 years, 57% female) that participated in the FDT from February 1, 2008 to January 31, 2015. Adjusting for clinical characteristics in a multivariate analysis, overall survival was compared for patients diagnosed with lung cancer within or outside the FDT in Iceland in 2014 (n=167, mean age 69.3 years, 61.7% female). Results: Of the 550 FDT patients, 426 were diagnosed with lung cancer (77.5%); 346 of the non-small cell type (NSCLC) (81.2%). The proportion of patients receiving lung cancer diagnosis through the FDT increased from 23.3% in 2008 to 47.9% in 2014 (p<0.001). The waiting time from referral to diagnosis was 10 days median and 19 days from diagnosis to initiation of treatment. More patients with advanced disease were diagnosed outside the FDT (70.1% vs. 37.5%, p<0.05). When ad­- justed for age, sex, histology, stage at diagnosis and therapy, patients diagnosed with lung cancer outside the FDT had higher risk of all-cause mortality (HR 1.60; 95% CI: 0.95 – 2.71) although the difference was not statistically significant. Conclusion: An increasing proportion of lung cancer diagnosis in Iceland is made through a fast diagnostic track with potential benefits for patients. The waiting time from referral to diagnosis and treatment is in line with international guidelinesVerkefnið hefur hlotið styrk vegna klínískra gæðaverkefna á Landspítala árið 2008 og verkefnastyrk frá RANNÍS (nr. 141667- 053)

Quantitative Dual-Energy Computed Tomography Supports a Vascular Etiology of Smoking-induced Inflammatory Lung Disease.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageEndothelial dysfunction is of interest in relation to smoking-associated emphysema, a component of chronic obstructive pulmonary disease (COPD). We previously demonstrated that computed tomography (CT)-derived pulmonary blood flow (PBF) heterogeneity is greater in smokers with normal pulmonary function tests (PFTs) but who have visual evidence of centriacinar emphysema (CAE) on CT.We introduced dual-energy CT (DECT) perfused blood volume (PBV) as a PBF surrogate to evaluate whether the CAE-associated increased PBF heterogeneity is reversible with sildenafil.Seventeen PFT-normal current smokers were divided into CAE-susceptible (SS; n = 10) and nonsusceptible (NS; n = 7) smokers, based on the presence or absence of CT-detected CAE. DECT-PBV images were acquired before and 1 hour after administration of 20 mg oral sildenafil. Regional PBV and PBV coefficients of variation (CV), a measure of spatial blood flow heterogeneity, were determined, followed by quantitative assessment of the central arterial tree.After sildenafil administration, regional PBV-CV decreased in SS subjects but did not decrease in NS subjects (P < 0.05), after adjusting for age and pack-years. Quantitative evaluation of the central pulmonary arteries revealed higher arterial volume and greater cross-sectional area (CSA) in the lower lobes of SS smokers, which suggested arterial enlargement in response to increased peripheral resistance. After sildenafil, arterial CSA decreased in SS smokers but did not decrease in NS smokers (P < 0.01).These results demonstrate that sildenafil restores peripheral perfusion and reduces central arterial enlargement in normal SS subjects with little effect in NS subjects, highlighting DECT-PBV as a biomarker of reversible endothelial dysfunction in smokers with CAE.NIH Bioengineering Research Partnership Grant/R01HL-112986 NIH MSTP training grant/5T32-GM00733

Analysis of pulmonary features and treatment approaches in the COPA syndrome.

The COPA syndrome is a monogenic, autoimmune lung and joint disorder first identified in 2015. This study sought to define the main pulmonary features of the COPA syndrome in an international cohort of patients, analyse patient responses to treatment and highlight when genetic testing should be considered. We established a cohort of subjects (N=14) with COPA syndrome seen at multiple centres including the University of California, San Francisco, CA, USA. All subjects had one of the previously established mutations in the COPA gene, and had clinically apparent lung disease and arthritis. We analysed cohort characteristics using descriptive statistics. All subjects manifested symptoms before the age of 12 years, had a family history of disease, and developed diffuse parenchymal lung disease and arthritis. 50% had diffuse alveolar haemorrhage. The most common pulmonary findings included cysts on chest computed tomography and evidence of follicular bronchiolitis on lung biopsy. All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity. All subjects received immunosuppressive therapy. COPA syndrome is an autoimmune disorder defined by diffuse parenchymal lung disease and arthritis. We analysed an international cohort of subjects with genetically confirmed COPA syndrome and found that common pulmonary features included cysts, follicular bronchiolitis and diffuse alveolar haemorrhage. Common extrapulmonary features included early age of onset, family history of disease, autoantibody positivity and arthritis. Longitudinal data demonstrated improvement on chest radiology but an overall decline in pulmonary function despite chronic treatment

Analysis of pulmonary features and treatment approaches in the COPA syndrome

The COPA syndrome is a monogenic, autoimmune lung and joint disorder first identified in 2015. This study sought to define the main pulmonary features of the COPA syndrome in an international cohort of patients, analyse patient responses to treatment and highlight when genetic testing should be considered. We established a cohort of subjects (N=14) with COPA syndrome seen at multiple centres including the University of California, San Francisco, CA, USA. All subjects had one of the previously established mutations in the COPA gene, and had clinically apparent lung disease and arthritis. We analysed cohort characteristics using descriptive statistics. All subjects manifested symptoms before the age of 12 years, had a family history of disease, and developed diffuse parenchymal lung disease and arthritis. 50% had diffuse alveolar haemorrhage. The most common pulmonary findings included cysts on chest computed tomography and evidence of follicular bronchiolitis on lung biopsy. All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity. All subjects received immunosuppressive therapy. COPA syndrome is an autoimmune disorder defined by diffuse parenchymal lung disease and arthritis. We analysed an international cohort of subjects with genetically confirmed COPA syndrome and found that common pulmonary features included cysts, follicular bronchiolitis and diffuse alveolar haemorrhage. Common extrapulmonary features included early age of onset, family history of disease, autoantibody positivity and arthritis. Longitudinal data demonstrated improvement on chest radiology but an overall decline in pulmonary function despite chronic treatment

Analysis of pulmonary features and treatment approaches in the COPA syndrome.

The COPA syndrome is a monogenic, autoimmune lung and joint disorder first identified in 2015. This study sought to define the main pulmonary features of the COPA syndrome in an international cohort of patients, analyse patient responses to treatment and highlight when genetic testing should be considered. We established a cohort of subjects (N=14) with COPA syndrome seen at multiple centres including the University of California, San Francisco, CA, USA. All subjects had one of the previously established mutations in the COPA gene, and had clinically apparent lung disease and arthritis. We analysed cohort characteristics using descriptive statistics. All subjects manifested symptoms before the age of 12 years, had a family history of disease, and developed diffuse parenchymal lung disease and arthritis. 50% had diffuse alveolar haemorrhage. The most common pulmonary findings included cysts on chest computed tomography and evidence of follicular bronchiolitis on lung biopsy. All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity. All subjects received immunosuppressive therapy. COPA syndrome is an autoimmune disorder defined by diffuse parenchymal lung disease and arthritis. We analysed an international cohort of subjects with genetically confirmed COPA syndrome and found that common pulmonary features included cysts, follicular bronchiolitis and diffuse alveolar haemorrhage. Common extrapulmonary features included early age of onset, family history of disease, autoantibody positivity and arthritis. Longitudinal data demonstrated improvement on chest radiology but an overall decline in pulmonary function despite chronic treatment