Inter‐rater reliability of phenotypes and exploratory genotype–phenotype analysis in inherited hidradenitis suppurativa

Abstract

Summary Background Genotype–phenotype correlation measures the correlation between the presence of a physical trait with a group of similar mutations but is dependent on reliable phenotyping. It can provide information on disease pathogenesis, future disease progression, severity or activity. Such indicators would be valuable in hidradenitis suppurativa (HS). Objectives To assess inter‐rater reliability (IRR) of HS clinical phenotypes and perform exploratory genotype–phenotype correlation in cases of HS with identified sequence variants. Methods Linkage disequilibrium between variants was assessed. Genotype–phenotype correlations were explored using Spearman correlation coefficients. IRR was calculated using Cohen's κ. Correlation between phenotype classifications was assessed using the χ2 statistic. Results Forty‐three sequence variants with clinical information were identified. Clinical phenotypes were classified as LC2 (n = 29; 67%), scarring folliculitis (n = 18; 42%), atypical (n = 38; 88%) and nodular (n = 26; 60%). LC1 phenotype was associated with regular (χ2 = 41·289, P < 0·001) and typical (χ2 = 29·013, P < 0·001) phenotypes. Cohen's κ was highest for van der Zee and Jemec (0·815), followed by Martorell‐Calatayud et al. (0·813), Naasan and Affleck (0·774) and Canoui‐Poitrine et al. (0·435) classifications. High linkage disequilibrium was seen between variants of Han Chinese pedigrees. No significant genotype–phenotype correlations were identified. Conclusions These findings may be influenced by selection, publication bias and the assumption that HS is a monogenic disorder. The poor IRR of existing phenotype measures suggests limited utility of existing measures. Further investigations into the correlation of clinical phenotypes with inflammatory biomarkers may aid in prognostic efforts for this disease. What's already known about this topic? Genotype–phenotype correlation can provide information regarding disease pathogenesis and predictions for future disease progression, severity or activity. The identification of such indicators in hidradenitis suppurativa (HS) would be valuable for patients and clinicians alike, given the lack of biomarkers or clinical predictors of disease. What does this study add? Sixty‐five sequence variants across 20 separate genes were identified. There was no significant correlation between phenotype classification in four separate classification schema and gene, mutation type or impact on Notch signalling. Utility of current phenotype measurements are limited. The lack of genotype–phenotype correlation in HS is suggestive that the underlying assumption of inherited HS as a monogenic disorder may need revision.

Lack of photographic documentation undermines assessment of hidradenitis suppurativa phenotypes: reply from the author

“…Dear Editor, We thank Dr van Straalen and Dr van der Zee for their response to our article . We agree that exploring genotype–phenotype correlation in inherited hidradenitis suppurativa (HS) is an important step in improving our understanding of the disease and optimizing patient care.…”

Genotype–phenotype correlation in inherited hidradenitis suppurativa: one step forward, one step back

“…In total, 32 out of 43 variants with sufficient clinical information had mutations in NCSTN and five mutations of PSTPIP1 . A weak but statistically significant inverse association was seen between the presence of the NCSTN sequence variant and latent class 1 (LC1) phenotype ( P = 0·038), and a significant association between the PSTPIP1 sequence variant and syndromic HS ( P = 0·001) was identified . High linkage disequilibrium was seen between variants of Han Chinese pedigrees, but this was limited by the rarity of variants.…”

“…This issue of the BJD includes an important study by Frew and colleagues regarding genotype–phenotype correlations in hidradenitis suppurativa (HS) . Frew et al .…”

“…proposed a phenotypic HS classification of latent classification (LC)1–3 and this was followed by three recent additional phenotypic classifications in 2015: van der Zee and Jemec, Naasan and Affleck, and Martorell‐Calatayud et al . Frew and colleagues used published data up to September 2018 and asked three experts to classify patients phenotypically based on clinical data and available patient photos while blinded to genetic information . There were significant correlations between some phenotype classifications, such as LC1 and regular and typical, and LC2 and follicular.…”

Coexistence of acne inversa with psoriasis and Dowling-Degos disease harboring impaired PSENEN-Notch signaling

“…To date, six mutations have been reported in PSENEN , all of which result in frameshift truncations and altered protein products, predominantly leading to haploinsufficiency. [ 2 ] Psoriasis is a genetically-determined proliferative and inflammatory entity, resulting from complex interactions between aberrant keratinocyte proliferation and differentiation, and a T-lymphocyte-mediated immune process. Dowling-Degos disease (DDD), a rare autosomal dominant disorder, is characterized by progressive reticulate hyperpigmentation and small dark-brown hyperkeratotic papules, mainly affecting flexural areas.…”