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Aggregate penetrance of genomic variants for actionable disorders in European and African Americans.

Abstract：

:In populations that have not been selected for family history of disease, it is unclear how commonly pathogenic variants (PVs) in disease-associated genes for rare Mendelian conditions are found and how often they are associated with clinical features of these conditions. We conducted independent, prospective analyses of participants in two community-based epidemiological studies to test the hypothesis that persons carrying PVs in any of 56 genes that lead to 24 dominantly inherited, actionable conditions are more likely to exhibit the clinical features of the corresponding diseases than those without PVs. Among 462 European American Framingham Heart Study (FHS) and 3223 African-American Jackson Heart Study (JHS) participants who were exome-sequenced, we identified and classified 642 and 4429 unique variants, respectively, in these 56 genes while blinded to clinical data. In the same participants, we ascertained related clinical features from the participants' clinical history of cancer and most recent echocardiograms, electrocardiograms, and lipid measurements, without knowledge of variant classification. PVs were found in 5 FHS (1.1%) and 31 JHS (1.0%) participants. Carriers of PVs were more likely than expected, on the basis of incidence in noncarriers, to have related clinical features in both FHS (80.0% versus 12.4%) and JHS (26.9% versus 5.4%), yielding standardized incidence ratios of 6.4 [95% confidence interval (CI), 1.7 to 16.5; P = 7 × 10-4) in FHS and 4.7 (95% CI, 1.9 to 9.7; P = 3 × 10-4) in JHS. Individuals unselected for family history who carry PVs in 56 genes for actionable conditions have an increased aggregated risk of developing clinical features associated with the corresponding diseases.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Natarajan P,Gold NB,Bick AG,McLaughlin H,Kraft P,Rehm HL,Peloso GM,Wilson JG,Correa A,Seidman JG,Seidman CE,Kathiresan S,Green RC

doi

10.1126/scitranslmed.aag2367

subject

Has Abstract

pub_date

2016-11-09 00:00:00

pages

364ra151

issue

364

eissn

1946-6234

issn

1946-6242

pii

8/364/364ra151

journal_volume

8

pub_type

杂志文章

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