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Mol Genet Genomic Med. 2016 Sep 17;4(6):604-616. eCollection 2016 Nov.

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

Author information

1
Department of Medical Genetics Oslo University Hospital and University of Oslo Oslo Norway.
2
Department of Immunology Oslo University Hospital Oslo Norway.
3
Institute of Clinical MedicineUniversity of OsloOsloNorway; Section of Clinical Immunology and Infectious DiseasesOslo University HospitalOsloNorway; Research Institute of Internal MedicineOslo University HospitalOsloNorway.
4
Department of Pediatrics Oslo University Hospital Oslo Norway.
5
Department of Medical BiochemistryInstitute of Clinical MedicineUniversity of OsloOsloNorway; Department of MicrobiologyOslo University HospitalOsloNorway.
6
Institute of Clinical MedicineUniversity of OsloOsloNorway; Department of PediatricsOslo University HospitalOsloNorway.
7
Department of Pediatrics Sørlandet Hospital Kristiansand Norway.
8
Human Genome Sequencing Center of Baylor College of Medicine Houston Texas.
9
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.
10
Baylor-Hopkins Center for Mendelian Genomics (BHCMG) of the Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas.
11
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.
12
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.
13
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.

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.

KEYWORDS:

Absence of heterozygosity; CARMIL2; RLTPR; exome sequencing; founder variant; lymphocyte function; lymphocyte subpopulation; molluscum contagiosum; primary immunodeficiency; warts

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