Compound Heterozygous CORO1A Mutations in Siblings with a Mucocutaneous-Immunodeficiency Syndrome of Epidermodysplasia Verruciformis-HPV, Molluscum Contagiosum and Granulomatous Tuberculoid Leprosy
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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.
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.
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.
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.
KeywordsCORO1A (Coronin-1A deficiency) SCID-CID HPV-epidermodysplasia verruciformis mucocutaneous molluscum leprosy telomere WES (whole exome sequencing)
This original work is in heartfelt memory of P1 and is dedicated to our CORO1A kindred. We graciously thank each of the medical and social service professionals of Texas Children’s Hospital and Baylor College of Medicine who contributed to the excellence in patient care, support, counseling and well-being of this CORO1A family and who continue to give their expertise and compassion on behalf of the affected siblings and their family members. Special appreciation is given to Drs. Robert Krance and Caridad Martinez, along with their team, of the Bone Marrow Transplantation Service of Texas Children’s Hospital-Baylor College of Medicine who are leading the transplantation efforts for the surviving sibling of this CORO1A kindred. With appreciation to Warren Leonard, MD, NIH Distinguished Investigator of the Laboratory of Molecular Immunology, National Institutes of Health, and to Karen Eldin, MD, Department of Pathology and Immunology of Baylor College of Medicine at Texas Children's Hospital. Collaboratively, the co-authors respectfully acknowledge all patients with primary immunodeficiencies and their families and express gratitude for the privilege of serving as their clinicians and scientists. This work was funded in part by Immunology, Allergy and Rheumatology of Texas Children’s Hospital-Department of Pediatrics of Baylor College of Medicine, the David Center and the Jeffrey Modell Diagnostic and Research Center to EMM, LMN and JSO the National Human Genome Research Institute, NIH Grant 5U54HG006542 to JRL and the Cancer Prevention Research Institute of Texas Grant RP120076 to AAB.
Conflict of Interest
The authors declare no conflict of interest.
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