Expanding our ethnic understanding of the genome

see Frequency and spectrum of actionable pathogenic secondary findings in 196 Korean exomes

Providing a reminder that genomics research must make more of an effort to include ethnic variation, a research team from South Korea reports on actionable findings based on exome data from 196 individuals of Korean origin. This first report of potentially actionable secondary findings in an Asian population applies ACMG evidence-based guidelines to classify the variants. Secondary findings in the Korean study population (7%) falls within the range of previously published studies in European and African subjects. For example, the 1000 Genomes Project found secondary findings in up to 11% of study subjects. Moreover, individuals in the healthy control group exhibited a proportion of pathogenic or likely pathogenic secondary variants (7%) statistically equivalent to that in individuals in the study group who were suspected of having a genetic disease (6%). The authors point out that while the ACMG guidelines for medically actionable genes are useful, they are not fully inclusive. For example, the ACMG list of 56 actionable genes does not include CDH1, which is the causative gene for hereditary diffuse gastric cancer and is of particular interest in the Asian population because of its high prevalence in that group. The study highlights the need to more fully explore the genetic diversity found in ethnic populations. Currently, genomic studies skew toward western Europeans, making any conclusions drawn from them inherently limited in scope and leaving other ethnic populations at a disadvantage in efforts to personalize medicine. —Karyn Hede, News Editor

IDIOM, a model program for rare-disease diagnosis

see A genome sequencing program for novel undiagnosed diseases

While many rare diseases are suspected to be of genetic origin, relatively few have been linked to a specific genetic origin. For patients and families, lack of diagnosis often leads to frustration. Now, a novel program modeled after the National Institutes of Health Undiagnosed Diseases Program is helping at least some individuals end their diagnostic odysseys. In this issue, the Scripps Idiopathic Diseases of Man (IDIOM) project reports on its first three years of operation. Of 121 cases reviewed for possible inclusion, 17 were ultimately selected for whole-genome sequencing. Of these, investigators were able to make a plausible molecular diagnosis in 10 cases. Three cases resulted in a confirmed molecular diagnosis. Of the confirmed cases, two led to identification of new gene–disease relationships. A third confirmed case was linked to a previously described but not fully characterized disorder. In all three cases, knowledge of the underlying genetic origin led to changes in treatment that had clinical benefit for the patients. The results suggest that genome sequencing could prove as useful for diagnosis of people with previously undescribed diseases as it is for diagnosis of known classic Mendelian disorders. The authors believe that IDIOM could provide a model for “application of genome sequencing across all rare genetic disorders, known and unknown.” —Karyn Hede, News Editor