NGS gene panel screening significantly improves diagnosis of congenital ichthyoses, a genetically heterogeneous group of keratinization disorders with more than 60 causative genes. However, it can occur that variants of uncertain significance (VUS) are detected and therefore no definitive diagnosis could be established. We report the case of a female patient with congenital ichthyosis and palmoplantar keratoderma, born to healthy caucasian non-consanguineous parents without any family history of ichthyosis. At birth she presented with erythroderma and rapidly developed fine white scales. Then she developed thicker scales and palmar hyperlinearity, without any other clinical abnormality. NGS panel (108 genes) analysis revealed in ABCA12 a pathogenic heterozygous missense mutation (c.4139A>G) inherited from the father and an in-frame deletion (c.7304_7306del) classified as a VUS inherited from the mother. Two other previously unreported heterozygous missense VUS were identified in DSG1 (c.3080T>C) and PERP (c.215C>T). The PERP VUS was predicted to affect a splicing acceptor site, thus leaning toward likely pathogenic. Our analysis of copy number variants (CNVs) revealed no gain or loss of DNA. In conclusion, the genetic variants we identified are compatible with the ichthyosis phenotype (ABCA12 heterozygous compound variants) as well as with the palmoplantar keratoderma (DSG1 and/or PERP heterozygous variants). But additional arguments of pathogenicity, provided in particular by in vitro functional assays, are needed to reclassify the VUS identified and determine whether they are responsible for the clinical phenotype of the patient.

ESDR308 - A case report illustrating the problem of VUS identification in the genetic diagnosis of congenital ichthyosis

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