Takahiro Hiraide1, Masaharu Kataoka2, Hisato Suzuki3, Yuki Aimi4, Tomohiro Chiba5, Sarasa Isobe1, Yoshinori Katsumata1, Shinichi Goto1, Kohsuke Kanekura6, Yoshitake Yamada7, Hidenori Moriyama1, Hiroki Kitakata1, Jin Endo1, Shinsuke Yuasa1, Yasumichi Arai8, Nobuyoshi Hirose8, Toru Satoh4, Yoji Hakamata9, Motoaki Sano1, Shinobu Gamou1, Kenjiro Kosaki3, Keiichi Fukuda1. 1. Department of Cardiology, Keio University School of Medicine, Tokyo, Japan. 2. Department of Cardiology, Keio University School of Medicine, Tokyo, Japan. Electronic address: m.kataoka09@keio.jp. 3. Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan. 4. Division of Cardiology, Second Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan. 5. Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan. 6. Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan. 7. Department of Diagnostic Radiology, Keio University School of Medicine, Tokyo, Japan. 8. Center for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo, Japan. 9. Department of Basic Sciences, Faculty of Veterinary Sciences, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, Japan.
Abstract
BACKGROUND: A variant of c.14429G>A (p.Arg4810Lys, rs112735431) in the ring finger protein 213 gene (RNF213; NM_001256071.2) has been recently identified as a risk allele for pulmonary arterial hypertension (PAH). PAH can be added as a new member of RNF213-associated vascular diseases, which include Moyamoya disease and peripheral pulmonary stenosis. Our aim was to identify the clinical features and outcomes of PAH patients with this variant. METHODS: Whole-exome sequencing was performed in 139 idiopathic (or possibly heritable) PAH patients. RESULTS: The RNF213 p.Arg4810Lys variant was identified in a heterozygous state in 11 patients (7.9%). Time-course changes in hemodynamics after combination therapy in the patients with the RNF213 p.Arg4810Lys variant were significantly poorer compared with those carrying the bone morphogenic protein receptor type 2 (BMPR2) mutation (n = 36) (comparison of changes in mean pulmonary arterial pressure, p = 0.007). The event-free rate of death or lung transplantation was significantly poorer in RNF213 p.Arg4810Lys variant carriers than in BMPR2 mutation carriers (5-year event-free rate since the introduction of prostaglandin I2 infusion, 0% vs 93%, respectively; p < 0.001). CONCLUSIONS: Idiopathic PAH patients with the RNF213 p.Arg4810Lys variant are associated with poor clinical outcomes even in recent times. Earlier consideration of lung transplantation might be required for RNF213 p.Arg4810Lys variant carriers who are developing PAH. Documentation of the RNF213 p.Arg4810Lys variant, as well as already known pathogenic genes, such as BMPR2, can provide clinically relevant information for therapeutic strategies, leading to a personalized approach for the treatment of PAH.
BACKGROUND: A variant of c.14429G>A (p.Arg4810Lys, rs112735431) in the ring finger protein 213 gene (RNF213; NM_001256071.2) has been recently identified as a risk allele for pulmonary arterial hypertension (PAH). PAH can be added as a new member of RNF213-associated vascular diseases, which include Moyamoya disease and peripheral pulmonary stenosis. Our aim was to identify the clinical features and outcomes of PAHpatients with this variant. METHODS: Whole-exome sequencing was performed in 139 idiopathic (or possibly heritable) PAHpatients. RESULTS: The RNF213p.Arg4810Lys variant was identified in a heterozygous state in 11 patients (7.9%). Time-course changes in hemodynamics after combination therapy in the patients with the RNF213p.Arg4810Lys variant were significantly poorer compared with those carrying the bone morphogenic protein receptor type 2 (BMPR2) mutation (n = 36) (comparison of changes in mean pulmonary arterial pressure, p = 0.007). The event-free rate of death or lung transplantation was significantly poorer in RNF213p.Arg4810Lys variant carriers than in BMPR2 mutation carriers (5-year event-free rate since the introduction of prostaglandin I2 infusion, 0% vs 93%, respectively; p < 0.001). CONCLUSIONS: Idiopathic PAHpatients with the RNF213p.Arg4810Lys variant are associated with poor clinical outcomes even in recent times. Earlier consideration of lung transplantation might be required for RNF213p.Arg4810Lys variant carriers who are developing PAH. Documentation of the RNF213p.Arg4810Lys variant, as well as already known pathogenic genes, such as BMPR2, can provide clinically relevant information for therapeutic strategies, leading to a personalized approach for the treatment of PAH.
Authors: Amélie Pinard; Maximillian D J Fiander; Alana C Cecchi; Andrea L Rideout; Mohamed Azouz; Stuart M Fraser; P Daniel McNeely; Simon Walling; Sarah C Novara; Anna C E Hurst; Dongchuan Guo; Sandhya Parkash; Michael J Bamshad; Deborah A Nickerson; Anthony M Vandersteen; Dianna M Milewicz Journal: Neurology Date: 2021-02-10 Impact factor: 9.910
Authors: R Mertens; M Graupera; H Gerhardt; A Bersano; E Tournier-Lasserve; M A Mensah; S Mundlos; P Vajkoczy Journal: Transl Stroke Res Date: 2021-09-16 Impact factor: 6.829