Clinical Presentation with High Penetrance in a Korean Family with Pulmonary Arterial Hypertension Associated with a BMPR2 Intron 3 Splice Site Pathogenic Variant

Mi-Jeong Kim; Seungok Lee; Dong Wook Jekarl; Hyojin Chae; Myungshin Kim; Hae-Ok Jung; Doo Soo Jeon

doi:10.3343/lmo.2018.8.3.119

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Kim, Lee, Jekarl, Chae, Kim, Jung, and Jeon: Clinical Presentation with High Penetrance in a Korean Family with Pulmonary Arterial Hypertension Associated with a BMPR2 Intron 3 Splice Site Pathogenic Variant

Original Article

Lab Med Online 2018;8(3):119-124.

Published online: 19 July 2018

DOI: https://doi.org/10.3343/lmo.2018.8.3.119

Clinical Presentation with High Penetrance in a Korean Family with Pulmonary Arterial Hypertension Associated with a BMPR2 Intron 3 Splice Site Pathogenic Variant

Mi-Jeong Kim, M.D.^1,², Seungok Lee, M.D.^3,⁴, Dong Wook Jekarl, M.D.^3,⁴, Hyojin Chae, M.D.^4,⁵, Myungshin Kim, M.D.^4,⁵, Hae-Ok Jung, M.D.^2,⁶, Doo Soo Jeon, M.D.^1,²

¹Division of Cardiology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea

²Division of Cardiology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea

³Department of Laboratory Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea

⁴Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea

⁵Catholic Genetic Laboratory Center, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea

⁶Division of Cardiology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea

Corresponding author: Seungok Lee Department of Laboratory Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 56 Dongsu-ro, Bupyung-gu, Incheon 21431, Korea Tel: +82-32-280-5512, Fax: +82-32-280-5520, E-mail: lsok@catholic.ac.kr

Received 9 September 2017 Revised 21 November 2017 Accepted 29 December 2017

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Pathogenic variants of bone morphogenic protein receptor type 2 gene (BMPR2) are related to the majority of cases of heritable pulmonary arterial hypertension (PAH). Over 400 pathogenic variants have been identified. However, clinical characterization of PAH is still incomplete. We present a case of heritable PAH in a Korean family showing serious clinical presentation with high penetrance. Genetic sequencing revealed a known heterozygous BMPR2 pathogenic variant, c.418+5G>A, at a splice site of intron 3. Serious clinical presentation with high penetrance suggested that the interplay of other factors with pathologic variants might be in genotype-phenotype correlation. Further studies are needed to clarify these issues for the development of personalized medicine approaches for PAH.

Keywords: Pulmonary hypertension, Bone morphogenetic protein receptor type 2, Pulmonary artery, Heritable pulmonary arterial hypertension

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Fig. 1.

Pedigree of the case family. The proband (II:3) was diagnosed with PAH later than her fourth (III:4) and fifth (III:5) daughters. Numbers in parentheses are age at death or current living age.

Fig. 2.

Chest radiograph, electrocardiogram, and echocardiogram of the proband at the time of PAH diagnosis. Cardiomegaly with bilateral hilar enlargement in chest radiograph (A), atrial fibrillation and right ventricular hypertrophy in electrocardiogram (B), right ventricular dilation and hypertrophy, interventricular septal bowing (arrowhead), resultant left ventricular compression, and small amount of pericardial effusion in echocardiography (C-E). Estimated systolic pulmonary arterial pressure from peak tricuspid regurgitation flow velocity is around 110 mmHg (F). Abbreviations: AO, aorta; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

Fig. 3.

Chest radiograph and echocardiogram of the proband's fourth daughter (III:4) and first daughter (III:1) at the time of PAH diagnosis. Cardiomegaly and hilar enlargement in X-ray (A, E), right ventricular dilation and hypertrophy, interventricular septal bowing to left ventricle (arrow head) in echocardiogram (B-D, F-H). Abbreviations: AO, aorta; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

Fig. 4.

Sequencing chromatogram of BMPR2 gene from proband (A), proband's first daughter (III:1, B), and unaffected third daughter 5 (III:3, C) showed identical heterozygous pathogenic variants c.418+5G>A in the splice site of intron 3.

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