Pulmonary vasculopathies: 1.2.1 BMPR2 3.3 Other pulmonary diseases - - PDF document

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Pulmonary vasculopathies: 1.2.1 BMPR2 3.3 Other pulmonary diseases - - PDF document

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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

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Pulmonary vasculopathies: From PAH to HHT

WENDY CHUNG, MD PHD

Kennedy Family Professor of Pediatrics and Medicine Columbia University

  • 3. PH DUE TO LUNG DISEASES AND/OR HYPOXIA

3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases

  • 4. CHRONIC THROMBOEMBOLIC PH
  • 5. PH WITH UNCLEAR MULTIFACTORIAL

MECHANISMS

5.1 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis, 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH

  • 1. PULMONARY ARTERIAL HYPERTENSION

1.1 Idiopathic PAH 1.2 Heritable PAH 1.2.1 BMPR2 1.2.2 ALK1, ENG, Smad 9, CAV1, KCNK3 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

1’. PULMONARY VENO-OCCLUSIVE DISEASE AND/OR PULMONARY CAPILLARY HEMANGIOMATOSIS 1’’. PERSISTENT PH OF THE NEWBORN

  • 2. PH DUE TO LEFT HEART DISEASE

2.1 LV systolic dysfunction 2.2 LV diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow tract

  • bstruction and congenital cardiomyopathies

5TH WORLD SYMPOSIUM CLASSIFICATION OF PH

SIMONNEAU G ET AL. J AM COLL CARDIOL. 2013;62:D34-D41.

  • 1. PULMONARY ARTERIAL HYPERTENSION

1.1 Idiopathic PAH 1.2 Heritable PAH 1.2.1 BMPR2 1.2.2 ALK1, ENG, Smad 9, CAV1, KCNK3 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

1’. PULMONARY VENO-OCCLUSIVE DISEASE (PVOD) AND/OR PULMONARY CAPILLARY HEMANGIOMATOSIS 1’’. PERSISTENT PH OF THE NEWBORN

GENETIC PROGRESS HAS FOCUSED ON GROUP 1: PAH

SIMONNEAU G ET AL. J AM COLL CARDIOL. 2013;62:D34-D41.

1998 2003 2008 2013 2018

Chromosome 2 locus identified

BMPR2

ALK1 ENG SMAD9 SMAD1 CAV1 KCNK3 TBX4

EIF2AK4 New genes! Linkage analysis in families and Sanger sequencing Whole exome sequencing Sequencing of candidate genes Whole genome sequencing

HISTORY OF GENETIC DISCOVERY IN HERITABLE PAH

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Smad 4 BMP9/10 BRE Targets (including ID1-4) TF(s)

PP

Smad5

PP

Cav1 Smad8

PP

Smad1

PP

Endoglin BMPRII ALK1

CAUSAL MUTATIONS IDENTIFIED TO DATE

KCNK3 EIF2AK4 HPAH PVOD/PCH TBX4

LEVELS OF EVIDENCE FOR PREVIOUSLY REPORTED PAH GENES

BMPR2 ALK1 (ACVRL1) ENG SMAD9 TBX4 KCNK3 CAV1 EIF2AK4 SMAD4 SMAD1 KLF2 BMPR1B GDF2 (BMP9) KCNA5

HIGH LEVEL OF EVIDENCE LOWER LEVEL OF EVIDENCE

Evidence may include: co-segregation, de novo mutation, functional studies

BMPR2 AND PAH

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% BMPR2 MUTATIONS INCREASE THE RISK OF PULMONARY HYPERTENSION BUT DO NOT GUARANTEE THE PERSON WILL EVER DEVELOP PULMONARY HYPERTENSION

  • 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

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DETERMINANTS OF PENETRANCE

* *

* *

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%)

BMPR2 MUTATION CARRIERS PRESENT WITH MORE SEVERE DISEASE

EVANS ET AL. LANCET RESPIR MED 2016

PAH WITH BMPR2 MUTATION: MORE SEVERE DISEASE

Vasodilator unresponsive

Worse cardiac performance

+/- Shorter survival

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.

BMPR2-PAH IPAH VASODILATOR RESPONSIVENESS

p=0.003

1/27 14/40

PERCENT VASOREACTIVE

50 40 30 20 10

NONSYNONYMOUS BMPR2 VARIATION NO NONSYNONYMOUS BMPR2 MUTATION

WORSE SURVIVAL IN BMPR2 MUTATION CARRIERS

EVANS ET AL. LANCET RESPIR MED 2016

p=0.002

TOTAL POPULATION

p<0.0001

AGE<50 AT DIAGNOSIS

No mutation Mutation

DEATH OR TRANSPLANTATION

No mutation Mutation

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HEREDITARY HEMORRHAGIC TELANGIECTASIA (HHT) AND PAH

AUTOSOMAL DOMINANT VASCULAR DISEASE

Mucocutaneous telangiectasias

Multiorgan AVMs

PAH rare, may proceed HHT dx

ALK1: TGFβ TYPE I RECEPTOR (≤ 10% PAH)

ENDOGLIN: ACCESSORY TGFβ RECEPTOR (< 1% PAH)

JOHNSON DW ET AL. NAT GENET. 1994;8:345-351. TREMBATH RC ET AL. N ENGL J MED. 2001;345:325-34.

ALK1-PAH MORE SEVERE

Shorter survival

Vasodilator unresponsive

Younger Dx & Death < BMPR2 mutation

Less severe hemodynamics

GIRERD B ET AL. AM J RESPIR CRIT CARE MED. 2010;181:851-61. 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

CUMULATIVE SURVIVAL (%) TIME TO DEATH (MONTHS) BMPR2/AVCRLI- BMPR2/+ AVCRLI+ p=<0.01

1 .8 .6 .4 .2

12 24 36 48 60 72 84 96 108 120 132 144

EXACT ESTIMATES OF FREQUENCY AMONG PAH PATIENTS TBD

RECENT MUTATION DISCOVERIES

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

AUSTIN ED ET AL. CIRC CARD RES. 2012 MA L ET AL. NEJM. 2013 BEST DH ET AL CHEST. 2014 EYRIES M ET AL. EUR RESP J. 2014

TASK-1 K+ K+

CAV1 MUTATIONS ARE A RARE CAUSE OF PAH +/- LIPODYSTROPHY

+

  • +

+ +

  • CAV1 c.474delA,

P158SPfsX22

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MUTATIONS IN KCNK3 ARE A RARE CAUSE OF FPAH AND IPAH: TWO-PORE DOMAIN POTASSIUM CHANNEL THAT SENSE O2 IN THE PULMONARY VASCULATURE

EYRIES ET AL. NATURE GENETICS 2014 BEST ET AL. CHEST 2014

RECESSIVE MUTATIONS IN EIF2AK4 IN ALL 13 FAMILIAL PVOD/PCH CASES BIALLELIC MUTATIONS IN 25% OF 20 SPORADIC PVOD/PCH CASES

EARLIER DISEASE ONSET, POOR RESPONSE TO THERAPY AND HIGH RATES OF TRANSPLANTATION IN BIALLELIC EIF2AK4 MUTATION CARRIERS

MONTANI ET AL. LANCET RESPIR MED 2017

Drug induced pulmonary edema in 23%

  • f mutation carriers

94 PVOD/PCH patients 28% carried biallelic EIF2AK4 mutations

BEST ET AL. CHEST 2017 HADINNAPOLA ET AL. CIRCULATION 2017

Age of onset (yrs) 39 51 49 29 31

PAH PATIENTS WITH BIALLELIC EIF2AK4 MUTATIONS ARE MISCLASSIFIED PVOD CASES

DLco (% predicted)

880 cases: IPAH = 808 FPAH = 56 PVOD =16

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4/21/2018 6

J MED GENET. 2013 AUG;50(8):500-6.

TBX4 mutations (n=3) or TBX4-containing deletions (n=3) were detected in 6 out

  • f 20 children with PAH

(30%) Not always associated with

  • bviously small patellas

TBX4 DELETIONS AND PAH TBX4 VARIANTS ARE LOSS OF FUNCTION

NH2

T-Box COOH

Q62X W77R M96K Indel IVS2-Ex3 c.355insA Y133C G248V R250W c.1112insC Y382S c.1164insC Q531R c.1070delC P98R R352X c.664delA T222fs c.537_546del:p.D179fs Q193X SPS mutations (7); Previous reported PAH mutations (5) PAH mutations: this study (9) S369fs R352L c.702+1, G>A Q62X W77R Indel IVS2-Ex3

New PAH genes

  • P-type ATPase (ATP13A3)
  • Growth and Differentiation Factor 9 (GDF2)
  • (BMP9)
  • SRY (Sex Determining Region Y) Box 17 (SOX17)

Smad 4

BMP9/10

BRE Targets (including ID1-4) TF

P P

Smad5

P P

Cav1 Smad8

PP

Smad1

PP

Endoglin BMPRII ALK1

MUTATIONS IDENTIFIED TO DATE IN HPAH AND PVOD

KCNK3 EIF2AK4

HPAH PVOD/PCH

TBX4 SOX17 ATP13A3

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4/21/2018 7

BMPR2 54% ACVRL1, ENG 8% TBX4 1% CAV1 1% EIF2AK4 2% Unexplained 36% BMPR2 9% ACVRL1, ENG 1% SMAD9 1% Unexplained 89% BMPR2 9% ACVRL1, ENG 1% TBX4 8% KCNK3 1% SMAD9 1% De novo 6% Unexplained 74% BMPR2 56% ACVRL1, ENG 12% TBX4 9% Unexplained 24%

RELATIVE CONTRIBUTION OF KNOWN RISK GENES AND DE NOVO MUTATIONS TO PEDIATRIC- AND ADULT-ONSET PAH

PEDIATRIC ADULT

Familial Non-familial

Familial Sporadic

REASONS TO PERFORM GENETIC TESTING

CONFIRM THE DIAGNOSIS

AVOID ADDITIONAL DIAGNOSTIC TESTING (LUNG BIOPSY)

REFINE PROGNOSIS

PREPARATION FOR FUTURE MOLECULARLY BASED TREATMENTS

INFORM RISK STRATIFICATION FOR FAMILY MEMBERS

Duty to inform

Facilitate early diagnosis of family members

INFORM REPRODUCTIVE OPTIONS

Preimplantation genetic diagnosis

ADDRESS PATIENT CONCERNS ABOUT ETIOLOGY: WHY ME?

RESOURCES TO ASSIST WITH GENETIC TESTING

FAMILY HISTORY TOOLS

Paper screening tools

https://familyhistory.hhs.gov/

EDUCATIONAL MATERIALS

Videos https://www.youtube.com/watch?v=36rlvtj_Qrs

GENETIC TESTING REGISTRY (HTTPS://WWW.NCBI.NLM.NIH.GOV/GTR/)

EASIER BIOLOGICAL SAMPLES (SALIVA, BUCCAL SWABS, AS WELL AS BLOOD)

TELEMEDICINE/VIDEO CONFERENCE OPTIONS FOR PRE-TEST AND POST- TEST EDUCATION AND GENETIC COUNSELING

Genetic counseling is critical for unaffected family members

WHO SHOULD HAVE GENETIC TESTING?

GROUP I PAH

 Familial PAH  IPAH (greatest number of BMPR2 mutation carriers

are in this group)

 Drugs/toxins  PVOD/PCH  Children

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WHAT TEST TO ORDER?

FAMILIAL MUTATION WHEN KNOWN

BMPR2 INCLUDING DELETION ANALYSIS

PANELS OF PAH GENES

EXOMES (AFTER A NEGATIVE PANEL)

 Familial cases  Pediatric/early onset cases (with parents to identify de

novo mutations)

VARIANTS OF UNCERTAIN SIGNIFICANCE

Frequency increases the more genes that are tested

Increased frequency in ethnic minorities

>95% of VUS identified on panel gene testing will be reclassified to benign

  • ver time

PANEL GENE TESTING ADVANTAGES

FULL COVERAGE (SEQUENCING AND DELETIONS WHICH ARE IMPORTANT FOR BMPR2)

GENES FOR PAH KNOWN AT THE TIME

TURN AROUND TIME 4-8 WEEKS

USE A LAB THAT RECLASSIFIES VUS PERIODICALLY

ClinVar as a resource

Exome Advantages/Differences

ABILITY TO ANALYZE NEW GENES OVER TIME AS THEY ARE IDENTIFIED

SOME LABORATORIES REANALYZE AN EXOME ONCE WITHOUT ADDITIONAL COST

ABLE TO REQUEST RAW EXOME DATA FOR REANALYSIS OR DONATION TO A RESEARCH STUDY

SECONDARY FINDINGS

 Support from a genetic professional helpful

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MANAGEMENT OF MUTATION POSITIVE/UNTESTED FAMILY MEMBERS

MONITORING SUGGESTIONS ARE NOT EVIDENCE BASED

 Annual echocardiogram 

IMMEDIATELY EVALUATE RESPIRATORY SYMPTOMS/SYNCOPE

FOR EIF2AK4 MEASURE DIFFUSION COEFFICIENT ON PULMONARY FUNCTION TESTS

GENETIC INFORMATION NON-DISCRIMINATION ACT (GINA) AND HEALTH INSURANCE

Health insurers can not require individuals to provide their genetic information to determine insurer for eligibility, coverage, underwriting, or premium-setting decisions

Genetic information cannot be used as a pre-existing condition (but PAH can)

GINA does not protect genetic discrimination in life insurance, disability insurance or long-term-care insurance

We Need More Data

CHICKEN OR THE EGG? WE NEED MORE RESEARCH DATA FOR CLINICAL UTILITY.

PATIENT WILL INCREASINGLY REQUEST GENETIC TESTING

RESEARCH REGISTRIES - DISEASE STRATIFIED BY MOLECULAR GENETICS

Natural history data

Clinical genomic data commons

Response to treatment

Option for return of genetic research results Inform clinical trials: disease stratification to identify responders/nonresponders

PREPARATION FOR MOLECULARLY BASED TREATMENT INCLUDING GENE BASED THERAPY

RECOMMENDATIONS

SCREEN FAMILIAL AND IDIOPATHIC CASES

 PAH gene panel testing  Clinical and echo screen family members q1-3 yrs 

SUSPICION OF PVOD AND/OR PCH

 EIF2AK4  testing could spare lung biopsy 

CHILDREN WITH COMPLEX DISEASE

 Consider exome sequencing

AUSTIN ED, LOYD JE. CIRC RES. 2014;115:189-200.

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CONCLUSIONS

 Genes play an important role in IPAH and FPAH  Many genes are involved, but the most common is

BMPR2

 There are many additional rare genetics causes of

PAH to be identified, especially in children

 Genetic testing is accessible to patients  Genetic testing is most helpful for risk stratification

  • f other family members and reproductive

planning, not guiding treatment

ACKNOWLEDGMENTS

  • Robyn Barst, MD
  • Jane Morse, MD
  • Erika Berman Rosenzweig, MD
  • Na Zhu, PhD
  • Carrie Welch, PhD
  • Yufeng Shen, PhD
  • Lijiang Ma, MD, PhD
  • Danilo Roman-Campos, PhD
  • Kevin Sampson PhD
  • Alain Borczuk, MD
  • Robert Kass, PhD
  • Eric Austin, MD
  • Dunbar Ivy, MD
  • Rizwan Hamid, MD
  • Bill Nichols, PhD
  • James Loyd, MD
  • Mélanie Eyries, PhD
  • Marine Germain, PhD
  • David-Alexandre Trégouët
  • Barbara Girerd MD
  • David Montani, MD, PhD
  • Florent Soubrier, MD, PhD
  • Nick Morrell, MD
  • Richard Trembath, MD
  • Marc Humbert, MD, PhD