A Genome Sequencing Program for Novel Undiagnosed Diseases

Purpose:The Scripps Idiopathic Diseases of Man (IDIOM) study aims to discover novel gene–disease relationships and provide molecular genetic diagnosis and treatment guidance for individuals with novel diseases using genome sequencing integrated with clinical assessment and multidisciplinary case review. Here we describe the operational protocol and initial results of the IDIOM study.Methods:A total of 121 cases underwent first-tier review by the principal investigators to determine whether the primary inclusion criteria were satisfied, 59 (48.8%) underwent second-tier review by our clinician–scientist review panel, and 17 patients (14.0%) and their family members were enrolled.Results:60% of cases resulted in a plausible molecular diagnosis, and 18% of cases resulted in a confirmed molecular diagnosis. Two of three confirmed cases led to the identification of novel gene–disease relationships. In the third confirmed case a previously described but unrecognized disease was revealed. In all three confirmed cases a new clinical management strategy was initiated based on the genetic findings.Conclusion:Genome sequencing provides tangible clinical benefit for individuals with idiopathic genetic disease, not only in the context of molecular genetic diagnosis of known rare conditions but also in cases where prior clinical information regarding a new genetic disorder is lacking.Genet Med 17 12, 995–1001.

[1]  Tina Pesaran,et al.  Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients , 2014, Genetics in Medicine.

[2]  P. Han,et al.  Mice lacking adenylyl cyclase‐5 cope badly with repeated restraint stress , 2009, Journal of neuroscience research.

[3]  David McHugh,et al.  Genetics in Medicine : Official Journal of the American College of Medical Genetics , 2011 .

[4]  Jeremy M. Harris,et al.  Genomics in Clinical Practice: Lessons from the Front Lines , 2013, Science Translational Medicine.

[5]  Joshua M. Korn,et al.  Discovery and genotyping of genome structural polymorphism by sequencing on a population scale , 2011, Nature Genetics.

[6]  Magalie S Leduc,et al.  Clinical whole-exome sequencing for the diagnosis of mendelian disorders. , 2013, The New England journal of medicine.

[7]  R. L. Bjork,et al.  De novo KCNB1 mutations in epileptic encephalopathy , 2014, Annals of neurology.

[8]  Daniel Nilsson,et al.  An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge , 2014, Genome Biology.

[9]  David P Bick,et al.  Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease , 2011, Genetics in Medicine.

[10]  A. Torkamani,et al.  ASXL1 and DNMT3A mutation in a cytogenetically normal B3 thymoma , 2014, Oncogenesis.

[11]  M. Bamshad,et al.  Genomics really gets personal: How exome and whole genome sequencing challenge the ethical framework of human genetics research , 2011, American journal of medical genetics. Part A.

[12]  Magalie S Leduc,et al.  Molecular findings among patients referred for clinical whole-exome sequencing. , 2014, JAMA.

[13]  M. Gerstein,et al.  CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. , 2011, Genome research.

[14]  R. Reading,et al.  Diagnostic exome sequencing in persons with severe intellectual disability , 2013 .

[15]  Rena A. Godfrey,et al.  The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases , 2011, Genetics in Medicine.

[16]  P. Stenson,et al.  Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics , 2010, Human mutation.

[17]  M. Daly,et al.  A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy , 2014, Nature Genetics.

[18]  H. Jacob,et al.  A timely arrival for genomic medicine , 2011, Genetics in Medicine.

[19]  B. V. van Bon,et al.  Diagnostic exome sequencing in persons with severe intellectual disability. , 2012, The New England journal of medicine.

[20]  Stef van Lieshout,et al.  Dominant missense mutations in ABCC9 cause Cantú syndrome , 2012, Nature Genetics.

[21]  K. Boycott,et al.  Rare-disease genetics in the era of next-generation sequencing: discovery to translation , 2013, Nature Reviews Genetics.

[22]  Siddharth Srivastava,et al.  Clinical whole exome sequencing in child neurology practice , 2014, Annals of neurology.

[23]  N. Schork,et al.  Gain‐of‐function ADCY5 mutations in familial dyskinesia with facial myokymia , 2014, Annals of neurology.