Familial hidradenitis suppurativa (fHS) is a chronic skin disease, in which γ-secretase mutations are implicated, although they account for few cases.1,2 Being HS is classified as an autoinflammatory keratinization disorder, we hypothesized that genetic susceptibility may arise from alterations affecting both epidermal barrier integrity and regulation of innate and adaptive inflammatory responses.3 We enrolled 25 patients with fHS and their families (54 affected and 17 healthy members) across European HS competence centers. 14 (56%) patients reported a disease onset before the age of 18 with 5 showing clinical manifestation before the age of 14 (Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/z9bxzsfv96/1). We performed Whole Exome Sequencing (WES) on 60 out of the 71 individuals. Variant selection emphasized functional relevance: rare (allele frequency<0.01/absent), heterozygous, exonic/splicing variants and predicted pathogenicity (CADD>15/absent) were retained if expressed in skin (GTEx) and co-segregating. Gene variants were ranked by functional relevance using Gene Ontology (GO) categories: inflammatory response (GO:0006954), keratinization (GO:0031424), epidermal homeostasis (GO:0036334), cell junction (GO:0030054), cell proliferation (GO:0008283), cell adhesion (GO:0007155), and antimicrobial activity (GO:0003795). Human Phenotype Ontology (HPO) was assessed for acne inversa (HP:0040154), cutaneous abscess (HP:0031292), recurrent abscesses (HP:0100838), draining sinus tract (HP:6000095), inflammatory skin abnormality (HP:0011123), abnormal keratinization/epidermal thickening (HP:0011368), and dermal neutrophilic infiltrate (HP:0031236). Each gene received a score of 1 per relevant GO category annotation (maximum score: 7) and additional score of 1 if at least 1 HS HPO term was present. The cumulative score (range: 0-8) reflects the potential biological involvement in HS pathogenesis, with higher scores indicating stronger functional and phenotypic relevance.
Epithelial barrier structure and adhesion gene variants in familial hidradenitis suppurativa across pediatric and adult cases / Tricarico, P.M., Moltrasio, C., Nardacchione, E.M., Jaschke, W., Moura, R., Boniotto, M., Roncarà, S., Margiotta, F.M., Caro, D.C., Genovese, G., Ghaffari, N., Von Stebut, E., Dini, V., Schmuth, M., Marzano, A.V., Crovella, S.. - In: JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY. - ISSN 0190-9622. - (2026), pp. ---. [10.1016/j.jaad.2026.09.042]
Epithelial barrier structure and adhesion gene variants in familial hidradenitis suppurativa across pediatric and adult cases
Tricarico, Paola Maura;Moltrasio, Chiara;Nardacchione, Elena Maria;Boniotto, Michele;Crovella, Sergio
2026-01-01
Abstract
Familial hidradenitis suppurativa (fHS) is a chronic skin disease, in which γ-secretase mutations are implicated, although they account for few cases.1,2 Being HS is classified as an autoinflammatory keratinization disorder, we hypothesized that genetic susceptibility may arise from alterations affecting both epidermal barrier integrity and regulation of innate and adaptive inflammatory responses.3 We enrolled 25 patients with fHS and their families (54 affected and 17 healthy members) across European HS competence centers. 14 (56%) patients reported a disease onset before the age of 18 with 5 showing clinical manifestation before the age of 14 (Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/z9bxzsfv96/1). We performed Whole Exome Sequencing (WES) on 60 out of the 71 individuals. Variant selection emphasized functional relevance: rare (allele frequency<0.01/absent), heterozygous, exonic/splicing variants and predicted pathogenicity (CADD>15/absent) were retained if expressed in skin (GTEx) and co-segregating. Gene variants were ranked by functional relevance using Gene Ontology (GO) categories: inflammatory response (GO:0006954), keratinization (GO:0031424), epidermal homeostasis (GO:0036334), cell junction (GO:0030054), cell proliferation (GO:0008283), cell adhesion (GO:0007155), and antimicrobial activity (GO:0003795). Human Phenotype Ontology (HPO) was assessed for acne inversa (HP:0040154), cutaneous abscess (HP:0031292), recurrent abscesses (HP:0100838), draining sinus tract (HP:6000095), inflammatory skin abnormality (HP:0011123), abnormal keratinization/epidermal thickening (HP:0011368), and dermal neutrophilic infiltrate (HP:0031236). Each gene received a score of 1 per relevant GO category annotation (maximum score: 7) and additional score of 1 if at least 1 HS HPO term was present. The cumulative score (range: 0-8) reflects the potential biological involvement in HS pathogenesis, with higher scores indicating stronger functional and phenotypic relevance.Pubblicazioni consigliate
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