title: Exome sequencing and unrelated findings in the context of complex disease research: ethical and clinical implications.
abstract: 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.
authors.affiliation: Department of Psychiatry, University of Utah, Salt Lake City, USA. lyong1@email.chop.edu
authors.forename: Gholson J
authors.initials: GJ
authors.lastname: Lyon
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Richard
authors.initials: R
authors.lastname: Van Wijk
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Paul Mark
authors.initials: PM
authors.lastname: Bodily
authors.forename: Jinchuan
authors.initials: J
authors.lastname: Xing
authors.forename: Lifeng
authors.initials: L
authors.lastname: Tian
authors.forename: Reid J
authors.initials: RJ
authors.lastname: Robison
authors.forename: Mark
authors.initials: M
authors.lastname: Clement
authors.forename: Yang
authors.initials: Y
authors.lastname: Lin
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Barry
authors.initials: B
authors.lastname: Moore
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Glessner
authors.forename: Josephine
authors.initials: J
authors.lastname: Elia
authors.forename: Fred
authors.initials: F
authors.lastname: Reimherr
authors.forename: Wouter W
authors.initials: WW
authors.lastname: van Solinge
authors.forename: Mark
authors.initials: M
authors.lastname: Yandell
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: William Evan
authors.initials: WE
authors.lastname: Johnson
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wei
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D000744:Anemia, Hemolytic, Autoimmune / Q000150:complications / Q000201:enzymology / Q000235:genetics; D001289:Attention Deficit Disorder with Hyperactivity / Q000150:complications / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D032984:Ethics, Research; D005091:Exons / Q000235:genetics*; D005260:Female; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D011770:Pyruvate Kinase / Q000737:chemistry / Q000235:genetics; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA / Q000379:methods*; D012984:Software
chemical_list: D011770:Pyruvate Kinase