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. 2015 Dec;17(12):995-1001.
doi: 10.1038/gim.2015.21. Epub 2015 Mar 19.

A genome sequencing program for novel undiagnosed diseases

Cinnamon S Bloss  1 , Ashley A Scott-Van Zeeland  2 , Sarah E Topol  1 , Burcu F Darst  1 , Debra L Boeldt  1 , Galina A Erikson  1 , Kelly J Bethel  3 , Robert L Bjork  4 , Jennifer R Friedman  5   6 , Nelson Hwynn  7 , Bradley A Patay  8 , Paul J Pockros  9 , Erick R Scott  1 , Ronald A Simon  10 , Gary W Williams  11 , Nicholas J Schork  1   12 , Eric J Topol  1   12   13 , Ali Torkamani  1   2   12   14
Affiliations

A genome sequencing program for novel undiagnosed diseases

Cinnamon S Bloss et al. Genet Med. 2015 Dec.

Erratum in

Abstract

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.

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Figures

Figure 1
Figure 1. Phenotypic Distribution of Case Referrals
The distribution of phenotypes referred to the Scripps IDIOM study is plotted based on the subset of N = 106 referrals for whom we were able to obtain complete data.
Figure 2
Figure 2. Tracking of Therapy Response in IDIOM1
Actigraphy based motion tracking demonstrates a dramatic and sustained decrease in night time myoclonic jerks due to gain of function mutation in ADCY5. Day 0 – 6 represents the last week of a three week run-in period to wash-out previous therapies. Diazepam is initiated on day 6 (arrow) with a dramatic reduction tremors sustained for over two months. Tremors are defined as movement magnitude >0 sustained for greater than 60 seconds.
See this image and copyright information in PMC

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