{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T08:33:32Z","timestamp":1762072412227,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,21]],"date-time":"2022-10-21T00:00:00Z","timestamp":1666310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gilead for the SAPH registry","award":["842001006"],"award-info":[{"award-number":["842001006"]}]},{"name":"ZonMw Topzorg","award":["842001006"],"award-info":[{"award-number":["842001006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: Pulmonary hypertension (PH) is a severe complication of sarcoidosis in a minority of patients. Several genetic defects are known to cause hereditary or sporadic PH, but whether variants in PH-associated genes are also involved in sarcoidosis-associated PH (SAPH) is unknown. Methods: 40 patients with SAPH were individually matched to 40 sarcoidosis patients without PH (SA). Whole exome sequencing was performed to identify rare genetic variants in a diagnostic PH gene panel of 13 genes. Additionally, an exploratory analysis was performed to search for other genes of interest. From 572 genes biologically involved in PH pathways, genes were selected in which at least 15% of the SAPH patients and no more than 5% of patients without PH carried a rare variant. Results: In the diagnostic PH gene panel, 20 different rare variants, of which 18 cause an amino-acid substitution, were detected in 23 patients: 14 SAPH patients carried a variant, as compared to 5 SA patients without PH (p = 0.018). Most variants were of yet unknown significance. The exploratory approach yielded five genes of interest. First, the NOTCH3 gene that was previously linked to PH, and furthermore PDE6B, GUCY2F, COL5A1, and MMP21. Conclusions: The increased frequency of variants in PH genes in SAPH suggests a mechanism whereby the presence of such a genetic variant in a patient may increase risk for the development of PH in the context of pulmonary sarcoidosis. Replication and studies into the functionality of the variants are required for further understanding the pathogenesis of SAPH.<\/jats:p>","DOI":"10.3390\/diagnostics12102564","type":"journal-article","created":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T02:31:03Z","timestamp":1666578663000},"page":"2564","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pulmonary Hypertension Associated Genetic Variants in Sarcoidosis Associated Pulmonary Hypertension"],"prefix":"10.3390","volume":"12","author":[{"given":"Karlijn","family":"Groen","sequence":"first","affiliation":[{"name":"Department of Pulmonology, St. Antonius ILD Center of Excellence, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marloes P.","family":"Huitema","sequence":"additional","affiliation":[{"name":"Department of Cardiology, St. Antonius Hospital Nieuwegein, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6727-8416","authenticated-orcid":false,"given":"Joanne J.","family":"van der Vis","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, St. Antonius ILD Center of Excellence, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands"},{"name":"Department of Clinical Chemistry, St. Antonius ILD Center of Excellence, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco C.","family":"Post","sequence":"additional","affiliation":[{"name":"Department of Cardiology, St. Antonius Hospital Nieuwegein, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands"},{"name":"Department of Cardiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan C.","family":"Grutters","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, St. Antonius ILD Center of Excellence, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands"},{"name":"Division of Hearts and Lungs, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert P.","family":"Baughman","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Coline H. M.","family":"van Moorsel","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, St. Antonius ILD Center of Excellence, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands"},{"name":"Division of Hearts and Lungs, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1164\/rccm.201006-0865CI","article-title":"A Concise Review of Pulmonary Sarcoidosis","volume":"183","author":"Baughman","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1183\/13993003.01032-2015","article-title":"2015 ESC\/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension","volume":"46","author":"Humbert","year":"2015","journal-title":"Eur. Respir. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1900897","DOI":"10.1183\/13993003.00897-2019","article-title":"Prevalence of Pulmonary Hypertension in Pulmonary Sarcoidosis: The First Large European Prospective Study","volume":"54","author":"Huitema","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1183\/09031936.05.00083404","article-title":"Pulmonary Hypertension in Advanced Sarcoidosis: Epidemiology and Clinical Characteristics","volume":"25","author":"Shorr","year":"2005","journal-title":"Eur. Respir. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1136\/thx.2005.042838","article-title":"Pulmonary Hypertension Associated with Sarcoidosis: Mechanisms, Haemodynamics and Prognosis","volume":"61","author":"Nunes","year":"2006","journal-title":"Thorax"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1016\/j.hlc.2021.03.279","article-title":"Clinical Phenotypes of Sarcoidosis-Associated Pulmonary Hypertension","volume":"30","author":"Mathijssen","year":"2021","journal-title":"Heart Lung Circ."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1378\/chest.128.3.1483","article-title":"Distinctive Clinical, Radiographic, and Functional Characteristics of Patients with Sarcoidosis-Related Pulmonary Hypertension","volume":"128","author":"Sulica","year":"2005","journal-title":"Chest"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1183\/09031936.00175907","article-title":"Clinical Predictors of Pulmonary Hypertension in Sarcoidosis","volume":"32","author":"Bourbonnais","year":"2008","journal-title":"Eur. Respir. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1007\/s12471-016-0847-1","article-title":"Pulmonary Hypertension Complicating Pulmonary Sarcoidosis","volume":"24","author":"Huitema","year":"2016","journal-title":"Neth. Heart J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1801371","DOI":"10.1183\/13993003.01371-2018","article-title":"Widening the Landscape of Heritable Pulmonary Hypertension Mutations in Paediatric and Adult Cases","volume":"53","author":"Eyries","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1038\/s41467-018-03672-4","article-title":"Identification of Rare Sequence Variation Underlying Heritable Pulmonary Arterial Hypertension","volume":"9","author":"Haimel","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_12","unstructured":"Austin, E.D., Phillips, J.A., and Loyd, J.E. (2022, September 02). Heritable Pulmonary Arterial Hypertension Overview, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/20301658\/."},{"key":"ref_13","first-page":"e19","article-title":"Estudio Cl\u00ednico y Molecular de 4 Casos de Hipertensi\u00f3n Pulmonar Asociada a Sarcoidosis","volume":"51","year":"2015","journal-title":"Arch. Bronconeumol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1038\/s41588-019-0528-2","article-title":"PanelApp Crowdsources Expert Knowledge to Establish Consensus Diagnostic Gene Panels","volume":"51","author":"Martin","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1034\/j.1399-3003.1999.14d02.x","article-title":"ATS\/ERS\/WASOG Statement on Sarcoidosis","volume":"14","author":"Costabel","year":"1999","journal-title":"Eur. Respir. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1136\/bmj.2.5261.1165","article-title":"Prognosis of Intrathoracic Sarcoidosis in England","volume":"2","author":"Scadding","year":"1961","journal-title":"BMJ"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"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","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s12863-016-0384-3","article-title":"Mutational and Clinical Analysis of the ENG Gene in Patients with Pulmonary Arterial Hypertension","volume":"17","author":"Pousada","year":"2016","journal-title":"BMC Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s00439-004-1196-5","article-title":"Hereditary Hemorrhagic Telangiectasia: ENG and ALK-1 Mutations in Dutch Patients","volume":"116","author":"Letteboer","year":"2005","journal-title":"Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1093\/eurheartj\/ehs442","article-title":"Genetic Variation in KCNA5: Impact on the Atrial-Specific Potassium Current IKur in Patients with Lone Atrial Fibrillation","volume":"34","author":"Christophersen","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1016\/j.jacc.2011.11.039","article-title":"Epistatic Effects of Potassium Channel Variation on Cardiac Repolarization and Atrial Fibrillation Risk","volume":"59","author":"Mann","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.clpt.2004.10.008","article-title":"Polymorphism Screening in the Cardiac K+ Channel Gene KCNA5*","volume":"77","author":"Simard","year":"2005","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1093\/hmg\/ddu531","article-title":"Functional Analysis of Endoglin Mutations from Hereditary Hemorrhagic Telangiectasia Type 1 Patients Reveals Different Mechanisms for Endoglin Loss of Function","volume":"24","author":"Mallet","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s00439-010-0825-4","article-title":"Update on Molecular Diagnosis of Hereditary Hemorrhagic Telangiectasia","volume":"128","author":"Grant","year":"2010","journal-title":"Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Sadick, H., Hage, J., Goessler, U., Stern-Straeter, J., Riedel, F., Hoermann, K., and Bugert, P. (2009). Mutation Analysis of \u201cEndoglin\u201d and \u201cActivin Receptor-like Kinase\u201d Genes in German Patients with Hereditary Hemorrhagic Telangiectasia and the Value of Rapid Genotyping Using an Allele-Specific PCR-Technique. BMC Med. Genet., 10.","DOI":"10.1186\/1471-2350-10-53"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"258","DOI":"10.2353\/jmoldx.2007.060117","article-title":"Clinical and Analytical Sensitivities in Hereditary Hemorrhagic Telangiectasia Testing and a Report of de Novo Mutations","volume":"9","author":"Gedge","year":"2007","journal-title":"J. Mol. Diagn."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ali, B.R., Ben-Rebeh, I., John, A., Akawi, N.A., Milhem, R.M., Al-Shehhi, N.A., Al-Ameri, M.M., Al-Shamisi, S.A., and Al-Gazali, L. (2011). Endoplasmic Reticulum Quality Control Is Involved in the Mechanism of Endoglin-Mediated Hereditary Haemorrhagic Telangiectasia. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0026206"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1136\/jmg.2006.042606","article-title":"Hereditary Haemorrhagic Telangiectasia: Mutation Detection, Test Sensitivity and Novel Mutations","volume":"43","author":"Prigoda","year":"2006","journal-title":"J. Med. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1182\/blood-2010-03-276881","article-title":"Functional Analysis of the BMP9 Response of ALK1 Mutants from HHT2 Patients: A Diagnostic Tool for Novel ACVRL1 Mutations","volume":"116","author":"Ricard","year":"2010","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/humu.20017","article-title":"Molecular Screening of ALK1\/ACVRL1 and ENG Genes in Hereditary Hemorrhagic Telangiectasia in France","volume":"23","author":"Lesca","year":"2004","journal-title":"Hum. Mutat."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"569","DOI":"10.2353\/jmoldx.2009.080148","article-title":"Multiple Sequence Variants in Hereditary Hemorrhagic Telangiectasia Cases: Illustration of Complexity in Molecular Diagnostic Interpretation","volume":"11","author":"McDonald","year":"2009","journal-title":"J. Mol. Diagn."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1016\/j.jvs.2017.02.034","article-title":"Variant Discovery in Patients with Mendelian Vascular Anomalies by Next-Generation Sequencing and Their Use in Patient Clinical Management","volume":"67","author":"Mattassi","year":"2018","journal-title":"J. Vasc. Surg."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s00408-015-9736-4","article-title":"A Semiconductor Chip-Based Next Generation Sequencing Procedure for the Main Pulmonary Hypertension Genes","volume":"193","author":"Reguero","year":"2015","journal-title":"Lung"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1136\/jmedgenet-2012-101152","article-title":"TBX4 Mutations (Small Patella Syndrome) Are Associated with Childhood-Onset Pulmonary Arterial Hypertension","volume":"50","author":"Bongers","year":"2013","journal-title":"J. Med. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1164\/rccm.201205-0886OC","article-title":"Longitudinal Analysis Casts Doubt on the Presence of Genetic Anticipation in Heritable Pulmonary Arterial Hypertension","volume":"186","author":"Larkin","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.1002\/art.10487","article-title":"Mutations of Bone Morphogenetic Protein Receptor Type II Are Not Found in Patients with Pulmonary Hypertension and Underlying Connective Tissue Diseases","volume":"46","author":"Tew","year":"2002","journal-title":"Arthritis Rheum."},{"key":"ref_37","first-page":"2379","article-title":"Pulmonary Hypertension in Scleroderma Spectrum of Disease: Lack of Bone Morphogenetic Protein Receptor 2 Mutations","volume":"29","author":"Morse","year":"2002","journal-title":"J. Rheumatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/mgg3.58","article-title":"Mutations of Notch3 in Childhood Pulmonary Arterial Hypertension","volume":"2","author":"Chida","year":"2014","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/bs.apha.2016.07.002","article-title":"Notch Signaling in Vascular Smooth Muscle Cells","volume":"78","author":"Baeten","year":"2017","journal-title":"Adv. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/nm.2021","article-title":"Notch3 Signaling Promotes the Development of Pulmonary Arterial Hypertension","volume":"15","author":"Li","year":"2009","journal-title":"Nat. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1700465","DOI":"10.1183\/13993003.00465-2017","article-title":"Management and Long-Term Outcomes of Sarcoidosis-Associated Pulmonary Hypertension","volume":"50","author":"Boucly","year":"2017","journal-title":"Eur. Respir. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1901747","DOI":"10.1183\/13993003.01747-2019","article-title":"Physiological Predictors of Survival in Patients with Sarcoidosis-Associated Pulmonary Hypertension: Results from an International Registry","volume":"55","author":"Shlobin","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Adzhubei, I., Jordan, D.M., and Sunyaev, S.R. (2013). Predicting Functional Effect of Human Missense Mutations Using PolyPhen-2, John Wiley & Sons, Inc.","DOI":"10.1002\/0471142905.hg0720s76"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1038\/nprot.2009.86","article-title":"Predicting the Effects of Coding Non-Synonymous Variants on Protein Function Using the SIFT Algorithm","volume":"4","author":"Kumar","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e118","DOI":"10.1093\/nar\/gkr407","article-title":"Predicting the Functional Impact of Protein Mutations: Application to Cancer Genomics","volume":"39","author":"Reva","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"W446","DOI":"10.1093\/nar\/gkab266","article-title":"MutationTaster2021","volume":"49","author":"Steinhaus","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s13073-021-00835-9","article-title":"CADD-Splice\u2014Improving Genome-Wide Variant Effect Prediction Using Deep Learning-Derived Splice Scores","volume":"13","author":"Rentzsch","year":"2021","journal-title":"Genome Med."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/12\/10\/2564\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:00:39Z","timestamp":1760144439000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/12\/10\/2564"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,21]]},"references-count":47,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["diagnostics12102564"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics12102564","relation":{},"ISSN":["2075-4418"],"issn-type":[{"type":"electronic","value":"2075-4418"}],"subject":[],"published":{"date-parts":[[2022,10,21]]}}}