4/21/2018 5TH WORLD SYMPOSIUM CLASSIFICATION OF PH 1. PULMONARY ARTERIAL HYPERTENSION 3. PH DUE TO LUNG DISEASES AND/OR HYPOXIA 1.1 Idiopathic PAH 3.1 Chronic obstructive pulmonary disease 1.2 Heritable PAH 3.2 Interstitial lung disease Pulmonary vasculopathies: 1.2.1 BMPR2 3.3 Other pulmonary diseases with mixed restrictive 1.2.2 ALK1, ENG, Smad 9, CAV1, KCNK3 and obstructive pattern 1.2.3 Unknown 3.4 Sleep-disordered breathing 1.3 Drug- and toxin-induced 3.5 Alveolar hypoventilation disorders From PAH to HHT 1.4 Associated with 3.6 Chronic exposure to high altitude 1.4.1 Connective tissue disease 3.7 Developmental lung diseases 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart diseases 4. CHRONIC THROMBOEMBOLIC PH 1.4.5 Schistosomiasis WENDY CHUNG, MD PHD 1’. PULMONARY VENO-OCCLUSIVE DISEASE 5. PH WITH UNCLEAR MULTIFACTORIAL AND/OR PULMONARY CAPILLARY MECHANISMS HEMANGIOMATOSIS Kennedy Family Professor of Pediatrics and Medicine 5.1 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy 1’’. PERSISTENT PH OF THE NEWBORN Columbia University 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis, 2. PH DUE TO LEFT HEART DISEASE 5.3 Metabolic disorders: glycogen storage disease, Gaucher 2.1 LV systolic dysfunction disease, thyroid disorders 2.2 LV diastolic dysfunction 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic 2.3 Valvular disease renal failure, segmental PH 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies SIMONNEAU G ET AL. J AM COLL CARDIOL . 2013;62:D34-D41. GENETIC PROGRESS HAS FOCUSED ON HISTORY OF GENETIC DISCOVERY GROUP 1: PAH IN HERITABLE PAH 1. PULMONARY ARTERIAL HYPERTENSION KCNK3 1.1 Idiopathic PAH TBX4 BMPR2 1.2 Heritable PAH EIF2AK4 New genes! 1.2.1 BMPR2 Chromosome 2 CAV1 ALK1 SMAD9 1.2.2 ALK1, ENG, Smad 9, CAV1, KCNK3 ENG locus identified SMAD1 1.2.3 Unknown 1.3 Drug- and toxin-induced 1.4 Associated with 1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart diseases 1.4.5 Schistosomiasis 2003 2013 2018 1998 1’. PULMONARY VENO-OCCLUSIVE DISEASE (PVOD) AND/OR PULMONARY CAPILLARY HEMANGIOMATOSIS 2008 1’’. PERSISTENT PH OF THE NEWBORN Linkage analysis in families Sequencing of Whole exome Whole genome and candidate genes sequencing sequencing Sanger sequencing SIMONNEAU G ET AL. J AM COLL CARDIOL . 2013;62:D34-D41. 1
4/21/2018 LEVELS OF EVIDENCE FOR CAUSAL MUTATIONS IDENTIFIED TO DATE PREVIOUSLY REPORTED PAH GENES KCNK3 HIGH LEVEL OF EVIDENCE LOWER LEVEL OF EVIDENCE BMP9/10 Cav1 BMPR2 SMAD4 ALK1 (ACVRL1) SMAD1 Endoglin ALK1 ENG KLF2 BMPRII SMAD9 BMPR1B TBX4 GDF2 (BMP9) KCNK3 KCNA5 PP PP PP EIF2AK4 CAV1 Smad5 Smad8 EIF2AK4 Smad1 Smad 4 TBX4 Targets Evidence may include: co-segregation, de novo mutation, functional studies TF(s) (including ID1-4) PP HPAH PVOD/PCH BRE BMPR2 MUTATIONS INCREASE THE RISK OF PULMONARY HYPERTENSION BUT DO NOT GUARANTEE THE PERSON WILL BMPR2 AND PAH EVER DEVELOP PULMONARY HYPERTENSION 60-70% of FPAH is due to BMPR2 mutations 10-20% of IPAH cases are due to BMPR2 mutations Lifetime penetrance of BMPR2 mutations is ~ 20% Individuals who have a BMPR2 gene mutation are at risk to develop PH but may never develop the disease. Currently there is NO way to determine if a person with a BMPR2 gene mutation will or will not develop PH 2
4/21/2018 BMPR2 MUTATION CARRIERS DETERMINANTS OF PENETRANCE PRESENT WITH MORE SEVERE DISEASE Nine studies reporting 1624 patients (Paris, Giessen, Shanghai, Beijing, Bologna, Nashville, Salt Lake City, Heidelberg, New York, Japan) * 458 BMPR2 mutation carriers 1166 BMPR2 mutation non-carriers * BMPR2 mutations detected in 18.6% (range 3.5-30%) with idiopathic PAH BMPR2 mutation detected in 77% (range 53-86%) with familial PAH * PAH patients with BMPR2 mutations: are younger at diagnosis (35±13 versus 42±17 years) * have a higher mPAP, PVR and lower cardiac index demonstrate less vasoreactivity (3% versus 12%) EVANS ET AL. LANCET RESPIR MED 2016 PAH WITH BMPR2 MUTATION: WORSE SURVIVAL IN MORE SEVERE DISEASE BMPR2 MUTATION CARRIERS VASODILATOR RESPONSIVENESS 50 40 14/40 PERCENT VASOREACTIVE AGE<50 AT DIAGNOSIS TRANSPLANTATION TOTAL POPULATION 30 p =0.003 No mutation No mutation 20 DEATH OR 10 1/27 Mutation Mutation 0 p=0.002 p<0.0001 NONSYNONYMOUS NO NONSYNONYMOUS BMPR2 VARIATION BMPR2 MUTATION BMPR2 -PAH IPAH Vasodilator unresponsive Worse cardiac performance +/- Shorter survival EVANS ET AL. LANCET RESPIR MED 2016 ELLIOTT CG ET AL. CIRCULATION. 2006; 113: 2509-2515. ROSENZWEIG EB ET AL. J HEART LUNG TRANSPLANT. 2008; 27:668-674. SZTRYMF B ET AL. AM J RESPIR CRIT CARE MED. 2008. 177:1377-83. PFARR N ET AL. RESP RES. 2011;12:99HTTP://RESPIRATORY- RESEARCH.COM/CONTENT/12/1/99. BRITTAIN CHEST 2013. 3
4/21/2018 ALK1-PAH MORE SEVERE HEREDITARY HEMORRHAGIC TELANGIECTASIA (HHT) AND PAH 1 Shorter survival .8 Vasodilator CUMULATIVE SURVIVAL (%) BMPR2/AVCRLI- AUTOSOMAL DOMINANT VASCULAR DISEASE unresponsive .6 Younger Dx & Death Mucocutaneous telangiectasias Multiorgan AVMs < BMPR2 mutation BMPR2/+ .4 Less severe hemodynamics PAH rare, may proceed HHT dx .2 AVCRLI+ ALK1: TGF β TYPE I RECEPTOR ( ≤ 10% PAH) p =<0.01 0 ENDOGLIN: ACCESSORY TGF β RECEPTOR (< 1% PAH) 0 12 24 36 48 60 72 84 96 108 120 132 144 TIME TO DEATH (MONTHS) BMPR2/ACVRLI- 227 225 193 166 134 114 99 84 73 56 40 33 26 BMPR2+ 91 82 70 63 50 44 37 30 25 23 18 13 9 ACVRLI+ 9 5 4 4 3 1 1 0 JOHNSON DW ET AL. NAT GENET. 1994;8:345-351. TREMBATH RC ET AL. N ENGL J MED. 2001;345:325-34. GIRERD B ET AL. AM J RESPIR CRIT CARE MED. 2010;181:851-61. RECENT MUTATION DISCOVERIES CAV1 MUTATIONS ARE A RARE CAUSE OF PAH +/- LIPODYSTROPHY EXACT ESTIMATES OF FREQUENCY AMONG PAH PATIENTS TBD Gene Name Specialized Information Caveolin-1 ( CAV1 ) Caveolin-1 1 Family & 1 IPAH Caveolar structure NO signaling KCNK3 TASK-1 3 Families & 3 IPAH pH sensitive potassium channel - - + + EIF2AK4 ( GCN2 ) Eukaryotic translation initiation factors superfamily member Association with recessive and sporadic forms of PVOD and PCH PVOD PCH + + K+ CAV1 c.474delA, TASK-1 P158SPfsX22 AUSTIN ED ET AL. CIRC CARD RES. 2012 MA L ET AL. NEJM. 2013 BEST DH ET AL CHEST. 2014 K+ EYRIES M ET AL. EUR RESP J. 2014 4
4/21/2018 MUTATIONS IN KCNK3 ARE A RARE CAUSE OF FPAH AND IPAH: TWO-PORE DOMAIN POTASSIUM CHANNEL THAT SENSE O2 IN THE PULMONARY VASCULATURE RECESSIVE MUTATIONS IN EIF2AK4 IN ALL 13 FAMILIAL PVOD/PCH CASES BIALLELIC MUTATIONS IN 25% OF 20 SPORADIC PVOD/PCH CASES EYRIES ET AL. NATURE GENETICS 2014 BEST ET AL. CHEST 2014 EARLIER DISEASE ONSET, POOR RESPONSE TO THERAPY PAH PATIENTS WITH BIALLELIC EIF2AK4 AND HIGH RATES OF TRANSPLANTATION IN MUTATIONS ARE MISCLASSIFIED PVOD CASES BIALLELIC EIF2AK4 MUTATION CARRIERS 94 PVOD/PCH patients DLco (% predicted) 28% carried biallelic EIF2AK4 mutations 880 cases: Drug induced pulmonary edema in 23% IPAH = 808 of mutation carriers FPAH = 56 PVOD =16 Age of onset (yrs) 39 51 49 29 31 BEST ET AL. CHEST 2017 MONTANI ET AL. LANCET RESPIR MED 2017 HADINNAPOLA ET AL. CIRCULATION 2017 5
4/21/2018 TBX4 DELETIONS AND PAH TBX4 VARIANTS ARE LOSS OF FUNCTION TBX4 mutations (n=3) or Indel IVS2-Ex3 Indel IVS2-Ex3 TBX4 -containing deletions c.1112insC (n=3) were detected in 6 out R250W Q62X Y133C G248V Q62X M96K of 20 children with PAH c.1164insC c.355insA (30%) W77R Q531R W77R Y382S SPS mutations (7); Previous reported Not always associated with PAH mutations (5) obviously small patellas T-Box COOH NH2 PAH mutations: S369fs this study (9) c.702+1, G>A P98R R352X c.664delA R352L T222fs c.1070delC Q193X c.537_546del:p.D179fs J MED GENET. 2013 AUG;50(8):500-6. MUTATIONS IDENTIFIED TO DATE IN HPAH AND PVOD New PAH genes P-type ATPase ( ATP13A3 ) BMP9 /10 Cav1 KCNK3 Growth and Differentiation Factor 9 ( GDF2 ) Endoglin ATP13A3 ( BMP9 ) ALK1 BMPRII SRY (Sex Determining Region Y) Box 17 ( SOX17 ) P PP PP P Smad5 Smad8 Smad1 EIF2AK4 Smad 4 TBX4 Targets TF (including ID1-4) SOX17 P P HPAH BRE PVOD/PCH 6
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