A potential founder variant in CARMIL2/RLTPR in three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction
Hanne S. Sorte , Liv T. Osnes , Børre Fevang , Pål Aukrust , Hans C. Erichsen , Paul H. Backe , Tore G. Abrahamsen , Ole B. Kittang , Torstein Øverland , Shalini N. Jhangiani , Donna M. Muzny , Magnus D. Vigeland , Pubudu Samarakoon , Tomasz Gambin , Zeynep H. C. Akdemir , Richard A. Gibbs , Olaug K. Rødningen , Robert Lyle , James R. Lupski , Asbjørg Stray-Pedersen
AbstractBackground 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 IFNγ -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.
|Journal series||Molecular Genetics & Genomic Medicine, ISSN , e-ISSN 2324-9269|
|Publication size in sheets||0.6|
|Score|| = 0.0, 27-08-2020, ArticleFromJournal|
= 5.0, 27-08-2020, ArticleFromJournal
|Publication indicators||= 23; = 20; = 31.0; : 2017 = 2.695 (2)|
|Citation count*||31 (2020-08-30)|
* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.