title: A potential founder variant inCARMIL2/RLTPRin three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction.
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 ofhuman 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.
  
  
  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 inCARMIL2(also known asRLTPR) 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.CARMIL2is 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 toCXCR4-,DOCK8-,GATA2-,MAGT1-,MCM4-,STK4-,RHOH-,TMC6-,andTMC8-related diseases. The specific variant may represent a Norwegian founder variant segregating on a population-specific haplotype.
authors.affiliation: Department of Medical Genetics Oslo University Hospital and University of Oslo Oslo Norway.
authors.forename: Hanne S
authors.initials: HS
authors.lastname: Sorte
authors.affiliation: Department of Immunology Oslo University Hospital Oslo Norway.
authors.forename: Liv T
authors.initials: LT
authors.lastname: Osnes
authors.affiliation: Institute of Clinical MedicineUniversity of OsloOsloNorway; Section of Clinical Immunology and Infectious DiseasesOslo University HospitalOsloNorway; Research Institute of Internal MedicineOslo University HospitalOsloNorway.
authors.forename: Børre
authors.initials: B
authors.lastname: Fevang
authors.affiliation: Institute of Clinical MedicineUniversity of OsloOsloNorway; Section of Clinical Immunology and Infectious DiseasesOslo University HospitalOsloNorway; Research Institute of Internal MedicineOslo University HospitalOsloNorway.
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.affiliation: Department of Pediatrics Oslo University Hospital Oslo Norway.
authors.forename: Hans C
authors.initials: HC
authors.lastname: Erichsen
authors.affiliation: Department of Medical BiochemistryInstitute of Clinical MedicineUniversity of OsloOsloNorway; Department of MicrobiologyOslo University HospitalOsloNorway.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Backe
authors.affiliation: Institute of Clinical MedicineUniversity of OsloOsloNorway; Department of PediatricsOslo University HospitalOsloNorway.
authors.forename: Tore G
authors.initials: TG
authors.lastname: Abrahamsen
authors.affiliation: Department of Pediatrics Sørlandet Hospital Kristiansand Norway.
authors.forename: Ole B
authors.initials: OB
authors.lastname: Kittang
authors.affiliation: Department of Pediatrics Oslo University Hospital Oslo Norway.
authors.forename: Torstein
authors.initials: T
authors.lastname: Øverland
authors.affiliation: Human Genome Sequencing Center of Baylor College of Medicine Houston Texas.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Human Genome Sequencing Center of Baylor College of Medicine Houston Texas.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Department of Medical Genetics Oslo University Hospital and University of Oslo Oslo Norway.
authors.forename: Magnus D
authors.initials: MD
authors.lastname: Vigeland
authors.affiliation: Department of Medical Genetics Oslo University Hospital and University of Oslo Oslo Norway.
authors.forename: Pubudu
authors.initials: P
authors.lastname: Samarakoon
authors.affiliation: Institute of computer scienceWarsaw University of TechnologyWarsawPoland; Baylor-Hopkins Center for Mendelian Genomics (BHCMG) of the Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: Baylor-Hopkins Center for Mendelian Genomics (BHCMG) of the Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas.
authors.forename: Zeynep H C
authors.initials: ZH
authors.lastname: Akdemir
authors.affiliation: Baylor-Hopkins Center for Mendelian Genomics (BHCMG) of the Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas; Human Genome Sequencing Center of Baylor College of MedicineHoustonTexas; Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Medical Genetics Oslo University Hospital and University of Oslo Oslo Norway.
authors.forename: Olaug K
authors.initials: OK
authors.lastname: Rødningen
authors.affiliation: Department of Medical Genetics Oslo University Hospital and University of Oslo Oslo Norway.
authors.forename: Robert
authors.initials: R
authors.lastname: Lyle
authors.affiliation: Baylor-Hopkins Center for Mendelian Genomics (BHCMG) of the Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas; Human Genome Sequencing Center of Baylor College of MedicineHoustonTexas; Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas; Department of PediatricsBaylor College of Medicine, and Texas Children's HospitalHoustonTexas.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Baylor-Hopkins Center for Mendelian Genomics (BHCMG) of the Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas; Norwegian National Unit for Newborn ScreeningDivision of Children and Adolescent MedicineOslo University HospitalOsloNorway.
authors.forename: Asbjørg
authors.initials: A
authors.lastname: Stray-Pedersen
keywords: Absence of heterozygosity; CARMIL2; RLTPR; exome sequencing; founder variant; lymphocyte function; lymphocyte subpopulation; molluscum contagiosum; primary immunodeficiency; warts