A potential founder variant in CARMIL2/RLTPR in three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction.

TitleA potential founder variant in CARMIL2/RLTPR in three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction.
Publication TypeJournal Article
Year of Publication2016
AuthorsSorte, HS, Osnes, LT, Fevang, B, Aukrust, P, Erichsen, HC, Backe, PH, Abrahamsen, TG, Kittang, OB, Øverland, T, Jhangiani, SN, Muzny, DM, Vigeland, MD, Samarakoon, P, Gambin, T, Akdemir, ZHC, Gibbs, RA, Rødningen, OK, Lyle, R, Lupski, JR, Stray-Pedersen, A
JournalMol Genet Genomic Med
Volume4
Issue6
Pagination604-616
Date Published2016 Nov
ISSN2324-9269
Abstract

BACKGROUND: Four patients from three Norwegian families presented with a common skin phenotype of warts, molluscum contagiosum, and dermatitis since early childhood, and various other immunological features. Warts are a common manifestation of human papilloma virus (HPV), but when they are overwhelming, disseminated and/or persistent, and presenting together with other immunological features, a primary immunodeficiency disease (PIDD) may be suspected.

METHODS AND RESULTS: The four patients were exome sequenced as part of a larger study for detecting genetic causes of primary immunodeficiencies. No disease-causing variants were identified in known primary immunodeficiency genes or in other disease-related OMIM genes. However, the same homozygous missense variant in CARMIL2 (also known as RLTPR) was identified in all four patients. In each family, the variant was located within a narrow region of homozygosity, representing a potential region of autozygosity. CARMIL2 is a protein of undetermined function. A role in T-cell activation has been suggested and the mouse protein homolog (Rltpr) is essential for costimulation of T-cell activation via CD28, and for the development of regulatory T cells. Immunophenotyping demonstrated reduced regulatory, CD4+ memory, and CD4+ follicular T cells in all four patients. In addition, they all seem to have a deficiency in IFN γ -synthesis in CD4+ T cells and NK cells.

CONCLUSIONS: We report a novel primary immunodeficiency, and a differential molecular diagnosis to CXCR4-,DOCK8-,GATA2-,MAGT1-,MCM4-,STK4-,RHOH-,TMC6-, and TMC8-related diseases. The specific variant may represent a Norwegian founder variant segregating on a population-specific haplotype.

DOI10.1002/mgg3.237
Alternate JournalMol Genet Genomic Med
PubMed ID27896283
PubMed Central IDPMC5118205