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• W3201767477 abstract "HomeCirculation: Genomic and Precision MedicineVol. 14, No. 5COL3A1 Missense Variant in a Patient Presenting With Hemoptysis Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBCOL3A1 Missense Variant in a Patient Presenting With Hemoptysis Ahsun Riaz, MD, Juan Pablo Portocarrero, MBBCh, Andrew Hoel, MD, Anjana Yeldandi, MD, Lisa Dellefave-Castillo, MS, James Paparello, MD, Jane DeMatte D′Amico, MD and Lisa D. Wilsbacher, MD, PhD Ahsun RiazAhsun Riaz Department of Radiology (A.R.), Northwestern University Feinberg School of Medicine, Chicago, IL. Search for more papers by this author , Juan Pablo PortocarreroJuan Pablo Portocarrero Department of Medicine (J.P.P., J.P., J.D.D., L.D.W.), Northwestern University Feinberg School of Medicine, Chicago, IL. Search for more papers by this author , Andrew HoelAndrew Hoel Department of Surgery (A.H.), Northwestern University Feinberg School of Medicine, Chicago, IL. Search for more papers by this author , Anjana YeldandiAnjana Yeldandi https://orcid.org/0000-0001-9593-5375 Department of Pathology (A.Y.), Northwestern University Feinberg School of Medicine, Chicago, IL. Search for more papers by this author , Lisa Dellefave-CastilloLisa Dellefave-Castillo https://orcid.org/0000-0001-6044-0559 Center for Genomic Medicine (L.D.-C.), Northwestern University Feinberg School of Medicine, Chicago, IL. Search for more papers by this author , James PaparelloJames Paparello https://orcid.org/0000-0002-0031-6166 Department of Medicine (J.P.P., J.P., J.D.D., L.D.W.), Northwestern University Feinberg School of Medicine, Chicago, IL. Search for more papers by this author , Jane DeMatte D′AmicoJane DeMatte D′Amico Department of Medicine (J.P.P., J.P., J.D.D., L.D.W.), Northwestern University Feinberg School of Medicine, Chicago, IL. Search for more papers by this author and Lisa D. WilsbacherLisa D. Wilsbacher Correspondence to: Lisa D. Wilsbacher, MD, PhD, Northwestern University Feinberg School of Medicine, Simpson Querrey Biomedical Research Center 8-404 303 E. Superior St, Chicago, IL 60611. Email E-mail Address: [email protected] https://orcid.org/0000-0002-3676-0680 Department of Medicine (J.P.P., J.P., J.D.D., L.D.W.), Northwestern University Feinberg School of Medicine, Chicago, IL. Feinberg Cardiovascular and Renal Research Institute (L.D.W.), Northwestern University Feinberg School of Medicine, Chicago, IL. Department of Pharmacology (L.D.W.), Northwestern University Feinberg School of Medicine, Chicago, IL. Search for more papers by this author Originally published30 Sep 2021https://doi.org/10.1161/CIRCGEN.121.003386Circulation: Genomic and Precision Medicine. 2021;14:e003386A 25-year-old man with a history of bicuspid aortic valve presented with 3 weeks of chest pain, dyspnea, and intermittent hemoptysis. Imaging showed a hydropneumothorax. He underwent video-assisted thoracoscopic surgical wedge resection, which demonstrated perivascular lymphohistiocytic aggregates with scattered giant cells (Figure [A]) and blood vessel elastic fiber disruption. Vasculitis workup revealed elevated C reactive protein and erythrocyte sedimentation rate, but antibodies and complements C3/C4 were normal. Fifteen months later, he experienced sudden right flank pain and syncope while traveling for work. Imaging revealed a retroperitoneal hematoma and multifocal irregularities, pseudoaneurysm, and contained rupture of the right renal artery (Figure [B]). The differential diagnosis at the time included fibromuscular dysplasia and segmental arterial mediolysis. Given clinical stability, no arteriography was done to assess for active bleeding.Download figureDownload PowerPointFigure. Lung histopathology, imaging, and family history.A, Lung biopsy revealed perivascular lymphohistiocytic aggregates with scattered giant cells. B, Computed tomography angiogram (CTA) of the abdomen demonstrated multifocal irregularities of right renal artery (arrows) and perinephric hematoma. C, CTA 4 wk later showed a 2.6 cm saccular aneurysm of the midright renal artery (arrow). D, The proband was the only affected family member. Genetic testing revealed a COL3A1 c.593G>A; p.Glu198Arg likely pathogenic variant in the proband. Cascade testing detected that his father was mosaic for the COL3A1 likely pathogenic variant.Upon returning home, he was referred for genetic testing given the presentations suggestive of either segmental arterial mediolysis or vascular Ehlers-Danlos Syndrome (vEDS).1 He reported recurrent right flank pain four weeks after the retroperitoneal bleed, and imaging showed a new 2.6 cm aneurysm of the right renal artery (Figure [C]). Due to the rapid aneurysmal degeneration, he underwent urgent aorta to right renal artery bypass surgery with a 6 mm heparin-bonded, externally reinforced polytetrafluoroethylene conduit via transabdominal midline laparotomy. The aorta and distal renal artery were free of obvious friability; however, adjacent venous structures were thin-walled and fragile. Genetic testing results returned 19 days after surgery and revealed a collagen type III alpha1 (COL3A1) c.593G>A (p.Gly198Glu) likely pathogenic variant, which confirmed the diagnosis of vEDS. At 2 years, renal function was normal, and magnetic resonance angiography demonstrated a patent bypass with no anastomotic degeneration or new arterial pathology.His family history includes a healthy 27-year-old sister, healthy 24-year-old brother, and 64-year-old mother with hypertension (Figure [D]). His 62-year-old father had sigmoid colon resection for diverticulitis at the age of 55 years, which was complicated by bowel perforation requiring bowel resection and colostomy. Both of the proband′s parents underwent COL3A1 genetic testing, which included full gene sequencing at ≥×50 depth (average ×350 depth) and deletion/duplication analyses. His father′s testing revealed possible mosaicism for the COL3A1 c.593G>A likely pathogenic variant, with a reported allele frequency range of 10% to 20% in leukocyte DNA. The proband′s siblings were tested based on this result and were negative. The proband′s father had a normal aorta and branch arteries on imaging. This report adds to 6 other cases of vEDS caused by a COL3A1 mutation inherited from a parent mosaic for the mutation.2The COL3A1 gene encodes collagen type III alpha1, which forms type III collagen homotrimers in triple-helical conformation. The proband′s COL3A1 variant was reported in one of 572 patients with genetically confirmed vEDS, and it was not observed in the Genome Aggregation Database.3,4 Glycine198 occurs in a Gly-Xaa-Yaa repeat within the triple-helical domain of COL3A1. Glycine missense variants in Gly-Xaa-Yaa repeats destabilize type III collagen structure and lead to aneurysm/dissection of the aorta and medium-sized arteries, bowel perforation, uterine rupture during pregnancy, and spontaneous pneumothorax.4 Compared with missense variants, those that disrupt COL3A1 splice donor/acceptor sites associate with poor outcomes, whereas those that cause mRNA instability and loss of COL3A1 protein associate with improved survival.4Pulmonary manifestations of vEDS, including spontaneous pneumothorax, hemothorax, cavitary lesions, pulmonary cysts, bronchiectasis, and bullous lung disease, may occur as the presenting symptom.5 A review of genetically confirmed vEDS cases found pneumothorax or hemothorax in 17 of 96 patients, with pneumothorax or hemothorax preceding the first arterial or bowel perforation in 12 patients and pneumothorax or hemothorax preceding the vEDS diagnosis in 14 patients.5Management of vEDS includes imaging of the head, neck, chest, abdomen, and pelvis every 6 to 12 months, avoidance of contact sports and isometric exercises, and blood pressure control. Beta-blockers and losartan are commonly used for a maximal blood pressure goal of 120/70. The third-generation beta-blocker celiprolol was proposed as a specific treatment for vEDS, but the United States Food and Drug Administration denied the manufacturer′s New Drug Application in 2019. Randomized, double-blinded trials will be critical to determine optimal medical therapies for vEDS.In summary, we present a case of vEDS in which the patient initially presented with pneumothorax and hemoptysis before developing a rapidly expanding arterial aneurysm. Genetic testing revealed a COL3A1 c.593G>A (p.Gly198Glu) likely pathogenic variant, which confirmed the diagnosis. Cascade genetic testing, performed at high sequencing depth, demonstrated possible mosaicism for the COL3A1 mutation in the proband′s father. Based on this result, genetic testing was appropriate for the proband′s siblings. This case highlights that a vEDS diagnosis often requires input from multiple disciplines. Furthermore, this case illustrates that genetic testing is warranted in patients <40 years old with primary spontaneous pneumothorax (ie, in the absence of chronic obstructive pulmonary disease or other anatomic defects). Finally, this case demonstrates that deep sequencing can identify mosaicism, which impacts genetic counseling recommendations for testing of other family members.The data that support the findings of this study are available from the corresponding author upon reasonable request. The study was approved by the Northwestern University Institutional Review Board (no. STU00104548-MOD0032) and the family members gave informed consent.Nonstandard Abbreviations and AcronymsvEDSVascular Ehlers-Danlos SyndromeSources of FundingThis work was supported by the National Kidney Foundation of Illinois (to J.B. Portocarrero).Disclosures None.FootnotesFor Sources of Funding and Disclosures, see page 670.Correspondence to: Lisa D. Wilsbacher, MD, PhD, Northwestern University Feinberg School of Medicine, Simpson Querrey Biomedical Research Center 8-404 303 E. Superior St, Chicago, IL 60611. Email lisa.[email protected]eduReferences1. Pickup MJ, Pollanen MS. Traumatic subarachnoid hemorrhage and the COL3A1 gene: emergence of a potential causal link.Forensic Sci Med Pathol. 2011; 7:192–197. doi: 10.1007/s12024-010-9205-6CrossrefMedlineGoogle Scholar2. Legrand A, Devriese M, Dupuis-Girod S, Simian C, Venisse A, Mazzella JM, Auribault K, Adham S, Frank M, Albuisson J, et al.. Frequency of de novo variants and parental mosaicism in vascular Ehlers-Danlos syndrome.Genet Med. 2019; 21:1568–1575. doi: 10.1038/s41436-018-0356-2CrossrefMedlineGoogle Scholar3. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, Collins RL, Laricchia KM, Ganna A, Birnbaum DP, et al.; Genome Aggregation Database Consortium.The mutational constraint spectrum quantified from variation in 141,456 humans.Nature. 2020; 581:434–443. doi: 10.1038/s41586-020-2308-7CrossrefMedlineGoogle Scholar4. Pepin MG, Schwarze U, Rice KM, Liu M, Leistritz D, Byers PH. Survival is affected by mutation type and molecular mechanism in vascular Ehlers-Danlos syndrome (EDS type IV).Genet Med. 2014; 16:881–888. doi: 10.1038/gim.2014.72CrossrefMedlineGoogle Scholar5. Shalhub S, Neptune E, Sanchez DE, Dua A, Arellano N, McDonnell NB, Milewicz DM. Spontaneous pneumothorax and hemothorax frequently precede the arterial and intestinal complications of vascular Ehlers-Danlos syndrome.Am J Med Genet A. 2019; 179:797–802. doi: 10.1002/ajmg.a.61094CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails October 2021Vol 14, Issue 5Article InformationMetrics Download: 78 © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.121.003386PMID: 34587764 Originally publishedSeptember 30, 2021 Keywordshemoptysisflank painrenal arteryhydropneumothoraxEhlers-Danlos syndromePDF download SubjectsAneurysmVascular DiseaseGenetics" @default.
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