Dramatic Clinical Improvement Described in Rare Skin Disease (ILVEN) That Has Previously Proved Highly Treatment-Resistant; Treatment Choice Guided by Molecular Genetic Dissection of Disease in Two Patients That Revealed Mosaic Mutations in CARD14 Gene

On Day 3 (Thursday, October 29) of the American Society of Human Genetics (ASHG) 2020 Virtual Annual Meeting (https://www.ashg.org/meetings/2020meeting/), one of the multiple stimulating morning sessions was “From Genes to Therapeutic Targets and Clinical Trials” (#031). Among the six presentations given during this session was a particularly interesting one titled “Molecular Genetic Dissection of Inflammatory Linear Verrucous Epidermal Naevus Leads to Successful Targeted Therapy,” delivered by Melissa Riachi (photo), PhD, Post-Doctoral Research Associate, Francis Crick Institute (UK). In the abstract to her talk, Dr. Riachi noted that inflammatory linear verrucous epidermal naevus (ILVEN) is a rare childhood disease characterized by Blaschko-linear erythematous scaly skin. The disease is highly pruritic, causes distressing disfigurement, and is so notoriously treatment-resistant that this characteristic forms part of the diagnostic criteria. The cause has been unknown, other than a recent single case of GJA1 mosaicism [Editor’s Note: GJA1 is the abbreviation for gap junction protein alpha 1.] Using deep next-generation whole exome sequencing of affected skin and blood, Dr. Riachi’s group discovered mosaic mutations in the gene CARD14 as the cause of ILVEN in two patients with treatment-resistant disease. [Editor’s Note: CARD14 is the acronym for caspase recruitment domain family member 14.] Functional characterization of patient cultured keratinocytes demonstrated two increased interleukins (IL-12A and IL-23A) at expression and protein levels in a non-NF-kB-dependent manner. Dramatic clinical improvement was seen with IL12/IL23-inhibitor ustekinumab, chosen as a direct result of the genetic finding.