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


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 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.

Author Hanne S. Sorte - [Oslo University Hospital]
Hanne S. Sorte,,
, Liv T. Osnes - [Oslo University Hospital]
Liv T. Osnes,,
, Børre Fevang - [Universitetet i Oslo]
Børre Fevang,,
, Pål Aukrust - [Universitetet i Oslo]
Pål Aukrust,,
, Hans C. Erichsen - [Oslo University Hospital]
Hans C. Erichsen,,
, Paul H. Backe - [Universitetet i Oslo]
Paul H. Backe,,
, Tore G. Abrahamsen - [Universitetet i Oslo]
Tore G. Abrahamsen,,
, Ole B. Kittang - [Sørlandet Hospital]
Ole B. Kittang,,
, Torstein Øverland - [Oslo University Hospital]
Torstein Øverland,,
, Shalini N. Jhangiani - Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas [Baylor College of Medicine]
Shalini N. Jhangiani,,
et al.`
Journal seriesMolecular Genetics & Genomic Medicine, ISSN , e-ISSN 2324-9269
Issue year2016
NoIssue 6
Publication size in sheets0.6
URL http://onlinelibrary.wiley.com/doi/10.1002/mgg3.237/full
Languageen angielski
Score (nominal)5
Score sourcejournalList
ScoreMinisterial score = 0.0, 27-08-2020, ArticleFromJournal
Ministerial score (2013-2016) = 5.0, 27-08-2020, ArticleFromJournal
Publication indicators WoS Citations = 23; Scopus Citations = 20; GS Citations = 31.0; WoS Impact Factor: 2017 = 2.695 (2)
Citation count*31 (2020-08-30)
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