COPA syndrome is a rare autosomal-dominant immune dysregulation disorder caused by pathogenic variants in the COPA gene, typically presenting with autoimmunity, arthritis, and interstitial lung disease. However, genotype–phenotype correlations remain incomplete, and variants of uncertain significance (VUS) may contribute to atypical or partial clinical phenotypes.
We report a family with a novel heterozygous COPA variant (c.2206G>A; p.Ala736Thr) identified through whole-exome sequencing in a father and his son. The son, a 20-year-old male, presented with recurrent soft-tissue abscesses (gluteal and thigh) and empyema requiring surgical intervention. He suffered from chronic psoriatic/eczema-like skin lesions for 5 years. Family history was remarkable for autoimmune diseases, including psoriasis/eczema in the father, paternal aunt, and cousins.
The father exhibited a long-standing chronic cutaneous condition initially labelled as atopic dermatitis, later reclassified as psoriasis, with suboptimal response to dupilumab and adalimumab therapy. Whole-exome sequencing of both individuals revealed the same heterozygous COPA variant, c.2206G>A (p.Ala736Thr), classified as a VUS. 13 out of 22 bioinformatic in silico programs predict a pathogenic effect for this variant. To the best of our knowledge, the variant has not been described in the literature so far. An allele frequency of this variant in the general population has not been documented (gnomAD v2.1.1 controls).
This report highlights a potentially novel COPA gene variant segregating within a family presenting inflammatory manifestations, including psoriasis and recurrent abscesses. While the clinical features diverge from classical COPA syndrome, the presence of immune dysregulation across generations suggests a possible contributory role of the p.Ala736Thr variant. Functional studies and further familial segregation analysis are warranted to clarify its pathogenicity and expand the phenotypic spectrum of COPA-associated disease.
