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Ascertainment of Pulmonary Arterial Hypertension (FPAH) Families with Numerous Affected Members

Lisa Wheeler

Eric Austin

Joy Cogan

John Newman

John Phillips III

James E. Loyd


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Conference: 2009 PH Resource Network Symposium

Release Date: 09.24.2009

Presentation Type: Abstracts

Lisa A. Wheeler, MT; Eric D. Austin, MD; Joy D. Cogan, PhD; John H. Newman, MD; John A. Phillips III, MD; James E. Loyd, MD
Vanderbilt University Medical Center, Nashville, TN

PURPOSEAscertain families to study transmission, clinical expression, penetrance and natural history of FPAH.

METHODSFamilies are recruited from our clinic or referred by healthcare providers and patient organizations such as the Pulmonary Hypertension Association. Following informed consent, data and samples are collected from patients/family members utilizing family and medical history questionnaires. Genealogy searches are optimized using family resources, local archives, and web based research. Data is maintained utilizing ProgenyGenetics software, MS Access and MS Excel.

RESULTSWhile we expected that most of our 131 FPAH families would have 2 or at most 3 affected members due to low penetrance, we find that 18/131 (14%) have > 6 (range 6-31) affected family members and 6/131 (4.5%) have > 10 affected individuals. Estimated penetrance in these families ranges from 20-40%. Kindreds with many patients in multiple generations improve the power to detect modifier genes, biomarkers and other disease affectors. Concerted longitudinal ascertainment enabled us to enlarge pedigrees and detect additional affecteds. Of the 154 FPAH kindreds ascertained since 1980, 131/154 (85%) provided a comprehensive family history and 112/154 (73%) provided research samples. Seventy-seven US families have been evaluated for BMPR2 mutations, 57/77 (74%) are positive, 20/77 (26%) are negative, 23 are pending further analysis. (Of the BMPR2-negative families, one has pulmonary capillary hemangiomatosis, 2 have PVOD, and 4 have unconfirmed IPAH diagnosis.) We found 489 affected cases with a 2.4 female/male ratio, and cumulative mortality shows deaths distributed across all ages. Interestingly, families with a confirmed BMPR2 mutation included 271 affecteds with a 2.8 female/male ratio. The ~2600 individuals in the bloodline of these families have at least a 1 in 10 lifetime risk to develop FPAH. Clinical BMPR2 genetic testing is available to assist these individuals in refining risk.

CONCLUSIONSConcerted longitudinal ascertainment is necessary to identify and benefit from the resources that large, heavily affected PAH families offer.