Challenges associated with diagnostic exome sequencing in liver diseases

Abstract

BackgroundWe investigated the diagnostic yield of exome sequencing in patients with liver diseases.MethodsWe retrospectively analyzed WES data for 10,801 individuals: 758 patients with CLD, 7,856 self-declared healthy controls (HC), and 2,187 patients with chronic kidney disease (CKD). We searched for variants in a total of 502 genes causing Mendelian disorders with a primary or secondary liver disease phenotype. Candidate variants were previously reported as pathogenic (P) or likely pathogenic (LP) in the Human Gene Mutation Database (HGMD) or ClinVar databases, or novel protein-truncating variants (PTV).ResultsCandidate pathogenic variants were initially identified in 19.9% of participants, most of which were attributable to previously reported pathogenic variants with implausibly high allele frequencies. After stringent filtering based on population minor allele frequency and variant annotation, P/LP variants were detected in 0.93% of the cohort, with a significant enrichment in the CLD cohort compared to the HC cohort (X2 test OR: 5.00, 95% CI:3.06-8.18). After two levels of manual annotation, the diagnostic rate of monogenic disorders was 5.7% in the CLD cohort, attributable to P/LP variants in 25 genes. We also identified concordant liver phenotypes for 15/22 kidney disease patients with P/LP variants in liver genes. Clinically confirmed sequencing results had many implications for management: familial testing for early diagnosis and management, preventative screening for associated comorbidities, such as aneurysm or cancer. Some patients with previously undiagnosed congenital disorders of glycosylation, would benefit from selective nutritional management.ConclusionsGene list-based WES analysis provided a 5.7% diagnostic rate among patients with CLD, with implications regarding their clinical care and that of their families.