NCSTN In-Frame Deletion in Maltese Patients With Hidradenitis Suppurativa

Abstract

ImportanceHidradenitis suppurativa (HS) is a complex trait that has a monogenic etiology in a subset of patients. Variation in genes that encode proteins of the γ secretase complex, particularly NCSTN, account for few patients who exhibit familial forms of HS. Thus far, extensive genotype-phenotype correlations have been lacking.ObjectiveTo establish the prevalence of the NCSTN:c.671_682del variant and explore potential genotype-phenotype associations in an ethnically Maltese HS cohort.Design, Setting, and ParticipantsThis cross-sectional study conducted from December 2021 to September 2022 included patients 18 years or older with a diagnosis of HS as defined by recurrent nodules, abscesses, and/or draining tunnels in typical (axilla, breast, groin, buttock, thighs, and inframammary folds) and less typical (scalp, ear pinnae, neck, arms, antecubital fossae) sites who were recruited from the sole national dermatology reference center servicing the Maltese archipelago. Clinical examination and targeted genetic analysis for an NCSTN deletion that was originally identified through whole-exome sequencing in a family with multigenerational disease were performed.ExposureRecruited patients were phenotyped and genotyped for the NCSTN:c.671_682del variant.Main Outcome and MeasuresTo determine the prevalence of the NCSTN:c.671_682del variant and establish possible genotype-phenotype associations in the ethnically Maltese HS cohort.ResultsA total of 113 patients with HS (56 women [49.6%]) met the inclusion criteria and were enrolled in this study. The median age of disease onset was 18 years (range, 7-62 years), and the median International Hidradenitis Suppurativa Severity Score System score was 4.39 (range, 1.0-64.0). The NCSTN variant was identified in the heterozygous state in 14 patients (12.4%) from 5 unrelated, nonconsanguineous families of Maltese ethnicity. The variant was not identified in an ethnically matched reference genomic data set of disease-free individuals. Variant carriers manifested HS symptoms earlier and were more likely to exhibit a distinctive HS phenotype, which was characterized by involvement of the scalp, neck, torso, and antecubital fossae. Despite manifesting similar clinical disease severity, variant carriers were more likely to require treatment with adalimumab.Conclusions and RelevanceThe results of this cross-sectional study suggest that monogenic variation in NCSTN is associated with HS in a subset of patients who have a distinct, atypical phenotype.

Advances Toward the Clinical Translation of Hidradenitis Suppurativa Genetic Studies

“…This study is noteworthy because, until now, all NCSTN variants identified in research participants with HS have been unique to families . The cohort used in the study by Mintoff et al consisted of individuals from 98 unrelated families, suggesting that this single variant is carried by 1 in 20 Maltese individuals with HS. This may help to explain the high prevalence of HS in Malta …”

“…In this issue of JAMA Dermatology , 2 HS genetic studies are reported. The first study investigates the prevalence of an NCSTN variant (an in-frame deletion) previously identified by the same author group . The second study identifies HS risk variant alleles in a GWAS conducted with nearly 2000 cases.…”

“…In the first report, Mintoff et al conducted a variant screening study in Malta. They previously identified an NCSTN variant in a Maltese mother and son, both affected by HS .…”

“…Importantly, leveraging these opportunities first requires experimental validation that the identified variant is pathogenic. In healthy people unaffected by HS, complex splicing patterns at the NCSTN locus create several different transcriptional isoforms, including several that lack the portion of the protein affected by the NCSTN mutation identified by Mintoff et al This leaves open the possibility that the mutation identified by Mintoff et al may not have any biological effects. Molecular characterization of the mutation’s effects will help to validate the pathogenicity of the mutation and to resolve the disease mechanism.…”

“…Both of the HS genetic studies reported in this issue of JAMA Dermatology set a solid foundation for future studies aimed at understanding the biological and clinical relevance of new HS genetic evidence. Each study suggests a series of experiments that will allow us to gain new knowledge about HS.…”