Open Access Highly Accessed Research article

Whole-exome sequencing of a pedigree segregating asthma

Andrew T DeWan1*, Kathryn Brigham Egan2, Karen Hellenbrand2, Keli Sorrentino2, Nicole Pizzoferrato1, Kyle M Walsh13 and Michael B Bracken2

Author Affiliations

1 Department of Chronic Disease Epidemiology, Yale School of Public Health, 60 College St, New Haven, CT 06520, USA

2 Center for Perinatal, Pediatric and Environmental Epidemiology, Yale University Schools of Public Health and Medicine, 1 Church Street, New Haven, CT 06510, USA

3 Current affiliation: Division of Cancer Epidemiology, University of California, San Francisco, CA, USA

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BMC Medical Genetics 2012, 13:95  doi:10.1186/1471-2350-13-95

Published: 9 October 2012



Despite the success of genome-wide association studies for asthma, few, if any, definitively causal variants have been identified and there is still a substantial portion of the heritability of the disease yet to be discovered. Some of this “missing heritability” may be accounted for by family-specific coding variants found to be segregating with asthma.


To identify family-specific variants segregating with asthma, we recruited one family from a previous study of asthma as reporting multiple asthmatic and non-asthmatic children. We performed whole-exome sequencing on all four children and both parents and identified coding variants segregating with asthma that were not found in other variant databases.


Ten novel variants were identified that were found in the two affected offspring and affected mother, but absent in the unaffected father and two unaffected offspring. Of these ten, variants in three genes (PDE4DIP, CBLB, and KALRN) were deemed of particular interest based on their functional prediction scores and previously reported function or asthma association. We did not identify any common risk variants segregating with asthma, however, we did observe an increase in the number of novel, nonsynonymous variants in asthma candidate genes in the asthmatic children compared to the non-asthmatic children.


This is the first report applying exome sequencing to identify asthma susceptibility variants. Despite having sequenced only one family segregating asthma, we have identified several potentially functional variants in interesting asthma candidate genes. This will provide the basis for future work in which more families will be sequenced to identify variants across families that cluster within genes.

Asthma; Whole-exome sequencing; PDE4DIP; CBLB; KALRN