Compound Heterozygous CORO1A Mutations in Siblings with a Mucocutaneous-Immunodeficiency Syndrome of Epidermodysplasia Verruciformis-HPV, Molluscum Contagiosum and Granulomatous Tuberculoid Leprosy

• Published in: Journal of clinical immunology 2014-10, Vol.34 (7), p.871-890
• Main Authors: Stray-Pedersen, Asbjorg, Jouanguy, Emmanuelle, Crequer, Amandine, Bertuch, Alison A., Brown, Betty S., Jhangiani, Shalini N., Muzny, Donna M., Gambin, Tomasz, Sorte, Hanne, Sasa, Ghadir, Metry, Denise, Campbell, Judith, Sockrider, Marianna M., Dishop, Megan K., Scollard, David M., Gibbs, Richard A., Mace, Emily M., Orange, Jordan S., Lupski, James R., Casanova, Jean-Laurent, Noroski, Lenora M.
• Format: Article
• Language: English
• Subjects: Adolescent; B-Lymphocytes - physiology; Biomedical and Life Sciences; Biomedicine; CD4-Positive T-Lymphocytes - physiology; Child; DNA Mutational Analysis; Epidermodysplasia Verruciformis - etiology; Epidermodysplasia Verruciformis - genetics; Female; Genetic Predisposition to Disease; Granuloma - complications; Granuloma - genetics; Heterozygote; Humans; Immunologic Memory - genetics; Immunology; Infectious Diseases; Internal Medicine; Killer Cells, Natural - physiology; Leprosy, Tuberculoid - complications; Leprosy, Tuberculoid - genetics; Male; Medical Microbiology; Microfilament Proteins - genetics; Mollusca; Molluscum Contagiosum - genetics; Mucous Membrane - pathology; Mucous Membrane - virology; Mutation - genetics; Original Research; Papillomavirus Infections - etiology; Papillomavirus Infections - genetics; Polymorphism, Genetic; Severe Combined Immunodeficiency - complications; Severe Combined Immunodeficiency - genetics; Siblings; Skin - pathology; Skin - virology; Telomere Shortening - genetics
• ISSN: 0271-9142; 1573-2592; 1573-2592
• DOI: 10.1007/s10875-014-0074-8

Purpose Coronin-1A deficiency is a recently recognized autosomal recessive primary immunodeficiency caused by mutations in CORO1A (OMIM 605000) that results in T-cell lymphopenia and is classified as T - B + NK + severe combined immunodeficiency (SCID). Only two other CORO1A -kindred are known to date, thus the defining characteristics are not well delineated. We identified a unique CORO1A -kindred. Methods We captured a 10-year analysis of the immune-clinical phenotypes in two affected siblings from disease debut of age 7 years. Target-specific genetic studies were pursued but unrevealing. Telomere lengths were also assessed. Whole exome sequencing (WES) uncovered the molecular diagnosis and Western blot validated findings. Results We found the compound heterozygous CORO1A variants: c.248_249delCT (p.P83RfsX10) and a novel mutation c.1077delC (p.Q360RfsX44) (NM_007074.3) in two affected non-consanguineous siblings that manifested as absent CD4CD45RA + (naïve) T and memory B cells, low NK cells and abnormally increased double-negative (DN) ϒδ T-cells. Distinguishing characteristics were late clinical debut with an unusual mucocutaneous syndrome of epidermodysplasia verruciformis-human papilloma virus (EV-HPV), molluscum contagiosum and oral-cutaneous herpetic ulcers; the older female sibling also had a disfiguring granulomatous tuberculoid leprosy. Both had bilateral bronchiectasis and the female died of EBV+ lymphomas at age 16 years. The younger surviving male, without malignancy, had reproducibly very short telomere lengths, not before appreciated in CORO1A mutations. Conclusion We reveal the third CORO1A -mutated kindred, with the immune phenotype of abnormal naïve CD4 and DN T-cells and newfound characteristics of a late/hypomorphic-like SCID of an EV-HPV mucocutaneous syndrome with also B and NK defects and shortened telomeres. Our findings contribute to the elucidation of the CORO1A -SCID-CID spectrum.