title: First identification ofKrüppel-like factor 2mutation in heritable pulmonary arterial hypertension.
abstract: Heritable pulmonary arterial hypertension (HPAH) is an autosomal dominantly inherited disease caused by mutations in thebone morphogenic protein receptor 2(BMPR2) gene and/or genes of its signalling pathway in approximately 85% of patients. We clinically and genetically analysed an HPAH family without mutations in previously described pulmonary arterial hypertension (PAH) genes. Clinical assessment included electrocardiogram, lung function, blood gas analysis, chest X-ray, laboratory testing, echocardiography and right heart catheterization in case of suspected disease. Genetic diagnostics were performed using a PAH-specific gene panel including all known 12 PAH genes and 20 further candidate genes by next-generation sequencing (NGS). HPAH was invasively confirmed in two sisters and their father who died aged 32 years. No signs of HPAH were detected in five first-degree family members. Both sisters were lung transplanted and remained stable during a follow-up of >20 years. We detected a novel missense mutation in theKrüppel-like factor 2(KLF2) likely leading to a disruption of gene function. The sameKLF2mutation has been described as a recurrent somatic mutation in B-cell lymphoma. Neither the healthy family members carried the mutation nor >120000 controls. These findings point toKLF2as a new PAH gene. Further studies are needed to assess frequency and implication ofKLF2mutations in PAH patients.
authors.affiliation: Centre for Pulmonary Hypertension, Thoraxclinic at the University Hospital Heidelberg, Röntgenstrasse 1, 69126 Heidelberg, Germany christina.eichstaedt@med.uni-heidelberg.de).|Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.|Translational Lung Research Centre Heidelberg (TLRC), German Centre for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Eichstaedt
authors.affiliation: Centre for Pulmonary Hypertension, Thoraxclinic at the University Hospital Heidelberg, Röntgenstrasse 1, 69126 Heidelberg, Germany.|Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.|Translational Lung Research Centre Heidelberg (TLRC), German Centre for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Jie
authors.initials: J
authors.lastname: Song
authors.affiliation: Research Unit for Genome Biology, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Rebecca Rodríguez
authors.initials: RR
authors.lastname: Viales
authors.affiliation: Centre for Pulmonary Hypertension, Thoraxclinic at the University Hospital Heidelberg, Röntgenstrasse 1, 69126 Heidelberg, Germany.|Translational Lung Research Centre Heidelberg (TLRC), German Centre for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Zixuan
authors.initials: Z
authors.lastname: Pan
authors.affiliation: Centre for Pulmonary Hypertension, Thoraxclinic at the University Hospital Heidelberg, Röntgenstrasse 1, 69126 Heidelberg, Germany.|Translational Lung Research Centre Heidelberg (TLRC), German Centre for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Benjamin
authors.affiliation: Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Fischer
authors.affiliation: Clinic for Pneumology, Hannover Medical School, Carl-Neuberg Str 1, 30623 Hannover and German Centre for Lung Research (DZL), Hannover, Germany.
authors.forename: Marius M
authors.initials: MM
authors.lastname: Hoeper
authors.affiliation: Clinic of Pulmonology, University Hospital Zurich, Rämistrasse 100, 8091 Zürich, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ulrich
authors.affiliation: Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hinderhofer
authors.affiliation: Centre for Pulmonary Hypertension, Thoraxclinic at the University Hospital Heidelberg, Röntgenstrasse 1, 69126 Heidelberg, Germany.|Translational Lung Research Centre Heidelberg (TLRC), German Centre for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Grünig
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D065627:Familial Primary Pulmonary Hypertension / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D015398:Signal Transduction / Q000235:genetics
chemical_list: C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors
keywords: Krüppel-like factor 2; genetic diagnostics; genetics; pulmonary arterial hypertension