Targeted-Capture Next-Generation Sequencing in Diagnosis Approach of Pediatric Cholestasis
Marion Almes, Anne Spraul, Mathias Ruiz, M Girard, Bertrand Roquelaure, Nolwenn Laborde, Frédèric Gottrand, A. Turquet, Thierry Lamireau, A. Dabadie, Marjorie Bonneton, Alice Thébaut, Babara Rohmer, Florence Lacaille, Pierre Broué, Alexandre Fabre, Karine Mention-Mulliez, Jérôme Bouligand, Emmanuel Jacquemin, Emmanuel Gonzalès
Abstract
BACKGROUND: Cholestasis is a frequent and severe condition during childhood. Genetic cholestatic diseases represent up to 25% of pediatric cholestasis. Molecular analysis by targeted-capture next generation sequencing (NGS) has recently emerged as an efficient diagnostic tool. The objective of this study is to evaluate the use of NGS in children with cholestasis. METHODS: Children presenting cholestasis were included between 2015 and 2020. Molecular sequencing was performed by targeted capture of a panel of 34 genes involved in cholestasis and jaundice. Patients were classified into three categories: certain diagnosis; suggested diagnosis (when genotype was consistent with phenotype for conditions without any available OMIM or ORPHANET-number); uncertain diagnosis (when clinical and para-clinical findings were not consistent enough with molecular findings). RESULTS: A certain diagnosis was established in 169 patients among the 602 included (28.1%). Molecular studies led to a suggested diagnosis in 40 patients (6.6%) and to an uncertain diagnosis in 21 patients (3.5%). In 372 children (61.7%), no molecular defect was identified. CONCLUSIONS: NGS is a useful diagnostic tool in pediatric cholestasis, providing a certain diagnosis in 28.1% of the patients included in this study. In the remaining patients, especially those with variants of uncertain significance, the imputability of the variants requires further investigations.