Pulmonary Vascular Disease |

KCNK3 Mutations Are Found in Patients With Pulmonary Arterial Hypertension Associated With Fenfluramine or Dexfenfluramine Ingestion FREE TO VIEW

Ikue Nakayama, MD; Mary Beth Scholand, MD; D. Best, PhD; Kelli Sumner, PhD; Wendy Chung, MD; Lynette Brown, MD; C Elliott, MD
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Department of Medicine, Intermountain Medical Center, Murray, UT

Chest. 2015;148(4_MeetingAbstracts):944A. doi:10.1378/chest.2274714
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SESSION TITLE: Pulmonary Arterial Hypertension Posters I

SESSION TYPE: Original Investigation Poster

PRESENTED ON: Wednesday, October 28, 2015 at 01:30 PM - 02:30 PM

PURPOSE: Pulmonary arterial hypertension (PAH) is a devastating disorder. Gene mutations and/or exposure to drugs increase the risk to develop PAH. An epidemic of PAH occurred in the United States after approximately 35 million patients were exposed to fenfluramine or dexfenfluramine. Only about 1 in 10,000 patients exposed to these anorexigens developed PAH, suggesting that heritable susceptibility factors were present. Mutations in KCNK3 can cause heritable PAH (HPAH). We asked whether KCNK3 mutations were potential susceptibility factors for PAH diagnosed after fenfluramine or dexfenfluramine exposure.

METHODS: We identified 36 patients who were diagnosed with PAH after ingestion of fenfluramine or dexfenfluramine, including 33 unrelated patients with no family history of PAH, an affected mother and daughter, and one man with a family history of PAH. DNA samples extracted from whole blood were tested for mutations in the coding regions of KCNK3 gene with 4 primer sets. PCR was performed with universal M13 sequencing primers and 1 μl of big dye. Analysis was done on an ABI 3730 instrument. In addition, patients were also tested for mutations in BMPR2.

RESULTS: We identified a novel frame shift KCNK3 mutation (c.7delC) in one of 33 unrelated patients diagnosed with PAH associated with fenfluramine or dexfluramine ingestion. This frame shift mutation is predicted to critically affect protein synthesis and is therefore pathogenic. The mother, her daughter and the man with a family member diagnosed with IPAH each had a BMPR2 mutation, and they did not have a KCNK3 mutation.

CONCLUSIONS: KCNK3 or BMPR2 gene mutations often coexisted with exposure to fenfluramine or dexfluramine in patients diagnosed with PAH.

CLINICAL IMPLICATIONS: ACCP consensus guidelines recommend that patients diagnosed with idiopathic PAH be advised of the availability of genetic testing and counseling because of the strong possibility that they harbor a PAH-causing mutation. The present data suggest that patients diagnosed with PAH associated with drug exposures should also be advised of the availability of genetic testing and counseling.

DISCLOSURE: D. Best: Employee: Medical Director at ARUP Laboratories, but my salary is fully supplied by the University of Utah Kelli Sumner: Employee: ARUP Laboratories Lynette Brown: Employee: Intermountain Medical Center C Elliott: Employee: Intermountain Medical Center The following authors have nothing to disclose: Ikue Nakayama, Mary Beth Scholand, Wendy Chung

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