Cystic fibrosis testing in a referral laboratory: Results and lessons from a six-year period

Journal of Clinical Bioinformatics 01/2013; 3(1):3. DOI: 10.1186/2043-9113-3-3
Source: PubMed


The recent introduction of high throughput sequencing technologies into clinical genetics has made it practical to simultaneously sequence many genes. In contrast, previous technologies limited sequencing based tests to only a handful of genes. While the ability to more accurately diagnose inherited diseases is a great benefit it introduces specific challenges. Interpretation of missense mutations continues to be challenging and the number of variants of uncertain significance continues to grow.

We leveraged the data available at ARUP Laboratories, a major reference laboratory, for the CFTR gene to explore specific challenges related to variant interpretation, including a focus on understanding ethnic-specific variants and an evaluation of existing databases for clinical interpretation of variants. In this study we analyzed 555 patients representing eight different ethnic groups. We observed 184 different variants, most of which were ethnic group specific. Eighty-five percent of these variants were present in the Cystic Fibrosis Mutation Database, whereas the Human Mutation Database and dbSNP/1000 Genomes had far fewer of the observed variants. Finally, 21 of the variants were novel and we report these variants and their clinical classifications.

Based on our analyses of data from six years of CFTR testing at ARUP Laboratories a more comprehensive, clinical grade database is needed for the accurate interpretation of observed variants. Furthermore, there is a particular need for more and better information regarding variants from individuals of non-Caucasian ethnicity.

Download full-text


Available from: Elaine Lyon,
  • [Show abstract] [Hide abstract]
    ABSTRACT: With the proliferation of affordable large-scale human genomic data come profound and vexing questions about management of such data and their clinical uncertainty. These issues challenge the view that genomic research on human beings can (or should) be fully segregated from clinical genomics, either conceptually or practically. Here we argue that the historical sharp distinction between clinical care and research is especially problematic in the context of large-scale genomic sequencing of people with suspected genetic conditions. Core goals of both enterprises (e.g., understanding genotype-phenotype relationships; generating an evidence base for genomic medicine) are more likely to be realized at a population scale if both those ordering and those undergoing sequencing for clinical reasons are routinely and longitudinally studied. Rather than relying on expensive and lengthy randomized clinical trials and meta-analyses, we propose leveraging nascent clinical-research hybrid frameworks into a broader, more permanent instantiation of exploratory medical sequencing. Such an investment could enlighten stakeholders about the real-life challenges posed by whole-genome sequencing, e.g., establishing the clinical actionability of genetic variants, returning "off-target" results to families, developing effective service delivery models and monitoring long-term outcomes.
    Clinical Genetics 07/2014; 87(4). DOI:10.1111/cge.12461 · 3.93 Impact Factor