Exome panel diagnostics in rare childhood liver disease – good but not good enough?

Motivation Diagnosis of rare liver diseases with genetic origin in children remains a challenging task, often due to unspecific symptoms and limited accessibility to comprehensive genetic testing. Previous work has shown efficacy of diagnosis rates for targeted gene-panel-analysis, using preselected patient cohorts based on phenotypes, mainly in cholestatic diseases. The aim of this work was to evaluate this efficacy for a heterogenous patient group with different phenotypes throughout all age subgroups.

Methods 56 patients (24 female, mean age: 47,5±69,3 months) were evaluated for unexplained liver disease in 11 pediatric hepatology centers in Germany. All underwent high-throughput-sequencing (targeted exome-panel-analysis performed at CeGaT Tuebingen between 2014-2020) with clinical interpretation of up to 128 genes. We subdivided this cohort according to the degree of phenotypic characterization before sequencing: I: phenotype associated with specific suspected clinical diagnosis; II: phenotype likely associated with specific group of diseases (e.g., PFIC); III: no association.

Results The diagnostic yield was 53,6%. Upon identification of a specific genotype in this group, a therapeutic concept could be established. The most common diagnosis was PFIC (n=10). The diagnostic yields in subgroups were I: 64%; II: 42%; III: 57%.

Conclusion The diagnostic yield was comparable to previous studies even though a heterogenous group without preselection was evaluated. We show that exome-panel-analysis can be effective even for patients in which phenotyping does not allow association to a specific suspected disease pre-genotyping. In the future (trio-)whole-genome-sequencing and/or transcriptome-sequencing may lead to further improve the diagnostic yield and potentially identify new disease-causing genes.

Publikationsverlauf

Artikel online veröffentlicht:
23. Januar 2024