Abstract
Recalcitrant warts, caused by human papillomaviruses (HPVs), can be a cutaneous manifestation of inborn error of immunity. This study investigated the clinical manifestations, immunodeficiency, single-gene susceptibility, and HPV repertoire in a consanguineous family with severe sinopulmonary infections and recalcitrant warts. Clinical and immunologic evaluations, including FACS and lymphocyte transformation test, provided evidence for immunodeficiency. Combined whole-exome sequencing and genome-wide homozygosity mapping were utilized to disclose candidate sequence variants. Whole-transcriptome sequencing was used to concomitantly investigate the HPV genotypes and the consequences of detected sequence variants in the host. The proband, a male aged 41 years, was found to be homozygous for the c.6delG, p.Lys2Asnfs∗17 variant in ICOS, encoding the inducible T-cell costimulator. This variant was located inside the 5 megabase of runs of homozygosity on 2q33.2. RNA sequencing confirmed the deleteriousness of the ICOS variant in three skin biopsies revealing significant downregulation of ICOS and its ligand, ICOSLG. Reads unaligned to the human genome were applied to 926 different viruses, and α-HPV57, β-HPV107, β-HPV14, and β-HPV17 were detected. Collectively, we describe a previously unrecognized inborn error of T-cell immunity to HPVs, indicating that autosomal recessive ICOS deficiency can underlie recalcitrant warts, emphasizing the immunologic underpinnings of recalcitrant warts at the nexus of human and viral genomic variation.