Exome sequencing and unrelated findings in the context of complex disease research: ethical and clinical implications.

Gholson J. Lyon, Tao Jiang, Richard Van Wijk, Wei Wang, Paul Mark Bodily, Jinchuan Xing, Lifeng Tian, Reid J. Robison, Mark Clement, Yang Lin, Peng Zhang, Ying Liu, Barry Moore, Joseph T. Glessner, Josephine Elia, Fred Reimherr, Wouter W. van Solinge, Mark Yandell, Hakon Hakonarson, Jun WangWilliam Evan Johnson, Zhi Wei, Kai Wang

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


Exome sequencing has identified the causes of several Mendelian diseases, although it has rarely been used in a clinical setting to diagnose the genetic cause of an idiopathic disorder in a single patient. We performed exome sequencing on a pedigree with several members affected with attention deficit/hyperactivity disorder (ADHD), in an effort to identify candidate variants predisposing to this complex disease. While we did identify some rare variants that might predispose to ADHD, we have not yet proven the causality for any of them. However, over the course of the study, one subject was discovered to have idiopathic hemolytic anemia (IHA), which was suspected to be genetic in origin. Analysis of this subject's exome readily identified two rare non-synonymous mutations in PKLR gene as the most likely cause of the IHA, although these two mutations had not been documented before in a single individual. We further confirmed the deficiency by functional biochemical testing, consistent with a diagnosis of red blood cell pyruvate kinase deficiency. Our study implies that exome and genome sequencing will certainly reveal additional rare variation causative for even well-studied classical Mendelian diseases, while also revealing variants that might play a role in complex diseases. Furthermore, our study has clinical and ethical implications for exome and genome sequencing in a research setting; how to handle unrelated findings of clinical significance, in the context of originally planned complex disease research, remains a largely uncharted area for clinicians and researchers.

Original languageEnglish (US)
Pages (from-to)41-55
Number of pages15
JournalDiscovery medicine
Issue number62
StatePublished - Jul 2011

All Science Journal Classification (ASJC) codes

  • General Medicine


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