Personalized genomic disease risk of volunteers

Personalized genomic disease risk of volunteers

1. Manuel L. Gonzalez-Garay^a,¹,
2. Amy L. McGuire^b,
3. Stacey Pereira^b, and
4. C. Thomas Caskey^c,¹

Author Affiliations

1. Contributed by C. Thomas Caskey, August 27, 2013 (sent for review July 11, 2013)

Significance

Replacing traditional methods for genetic testing of inheritable disorders with next-generation sequencing (NGS) will reduce the cost of genetic testing and increase the information available for the patients. NGS will become an invaluable resource for the patient and physicians, especially if the sequencing information is stored properly and reanalyzed as bioinformatics tools and annotations improve. NGS is still at the early stages of development, and it is full of false-positive and -negative results and requires infrastructure and specialized personnel to properly analyze the results. This paper will explain our experience with an adult population, our bioinformatics analysis, and our clinical decisions to assure that our genetic diagnostics were accurate to detect carrier status and serious medical conditions in our volunteers.

Abstract

Next-generation sequencing (NGS) is commonly used for researching the causes of genetic disorders. However, its usefulness in clinical practice for medical diagnosis is in early development. In this report, we demonstrate the value of NGS for genetic risk assessment and evaluate the limitations and barriers for the adoption of this technology into medical practice. We performed whole exome sequencing (WES) on 81 volunteers, and for each volunteer, we requested personal medical histories, constructed a three-generation pedigree, and required their participation in a comprehensive educational program. We limited our clinical reporting to disease risks based on only rare damaging mutations and known pathogenic variations in genes previously reported to be associated with human disorders. We identified 271 recessive risk alleles (214 genes), 126 dominant risk alleles (101 genes), and 3 X-recessive risk alleles (3 genes). We linked personal disease histories with causative disease genes in 18 volunteers. Furthermore, by incorporating family histories into our genetic analyses, we identified an additional five heritable diseases. Traditional genetic counseling and disease education were provided in verbal and written reports to all volunteers. Our report demonstrates that when genome results are carefully interpreted and integrated with an individual’s medical records and pedigree data, NGS is a valuable diagnostic tool for genetic disease risk.

• molecular medicine
• disease prediction
• whole exome sequencing

Footnotes

• ¹To whom correspondence may be addressed. E-mail: Manuel.L.GonzalezGaray@uth.tmc.edu or tcaskey@bcm.edu.

• Author contributions: M.L.G.-G. and C.T.C. designed research; M.L.G.-G., A.L.M., S.P., and C.T.C. performed research; M.L.G.-G. analyzed data; and M.L.G.-G., A.L.M., S.P., and C.T.C. wrote the paper.
• The authors declare no conflict of interest.
• This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1315934110/-/DCSupplemental.

Freely available online through the PNAS open access option.