Abstract
BackgroundThe 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.ResultsWe 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.ConclusionsBased 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.
Highlights
The recent introduction of high throughput sequencing technologies into clinical genetics has made it practical to simultaneously sequence many genes
Whole genome sequencing studies have shown that each individual harbors 2.7–4.2 million single nucleotide variants (SNVs) that differ from the human reference genome [1], whereas exome sequencing typically identifies 18–24,000 coding region based SNVs per individual [2,3,4,5,6,7]
While guidelines exist to assist in SNV annotation and functional prediction [11,12,13,14], many novel variants continue to be classified as variants of uncertain significance (VUS)
Summary
The recent introduction of high throughput sequencing technologies into clinical genetics has made it practical to simultaneously sequence many genes. As a greater number of exomes and genomes are sequenced, having a more comprehensive catalogue of human genetic variation will facilitate individual gene variant classification. In our referral laboratory setting, we chose to study the cystic fibrosis transmembrane conductance regulator (CFTR) gene, representing a high volume full gene sequencing diagnostic assay. It should be noted, that at ARUP Laboratories, most cases have previously undergone testing with a 32-mutation panel identifying the most common disease-causing alleles, before sequencing. Mutations in CFTR are known to result in multiple conditions, ranging from classic cystic fibrosis (CF) to monosymptomatic diseases such as congenital absence of the vas deferens, pancreatitis, or chronic bronchiectasis
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