Interpreting the spectrum of gamma-secretase complex missense variation in the context of hidradenitis suppurativa—An in-silico study

Mintoff, Dillon; Pace, Nikolai Paul; Borg, Isabella

doi:10.3389/fgene.2022.962449

Cited by 9 publications

(9 citation statements)

References 82 publications

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“…In contrast to other complex traits, the contribution of noncoding or regulatory genomic variants and polygenic risk scores to HS is unknown. The GSC bears a high burden of rare deleterious variants in the gno-mAD reference data set 4 that can be associated with lateonset disease and confound variant classification. 18 Thus, rare or novel nonsynonymous variants are often classified as VUS, limiting their interpretation and clinical actionability.…”

Section: Discussionmentioning

confidence: 99%

“…Hidradenitis suppurativa is a heritable trait, with up to 35% of patients having a family history . Variants in genes encoding the γ secretase complex (GSC) proteins (primarily NCSTN ) are implicated in most familial HS cases that have an underlying monogenic etiology. The GSC functions in Notch regulation, which plays a pivotal role in follicular differentiation and epidermal homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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NCSTN In-Frame Deletion in Maltese Patients With Hidradenitis Suppurativa

2023

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NCSTN In-Frame Deletion in Maltese Patients With Hidradenitis Suppurativa

2023

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“… 26 The majority of variants implicated in HS involve one of the four γ-secretase complex (GSC) genes but predominantly NCSTN. 27 …”

Section: Epidemiology Of the Hidradenitis Suppurativamentioning

confidence: 99%

“…26 The majority of variants implicated in HS involve one of the four γ-secretase complex (GSC) genes but predominantly NCSTN. 27 Besides a link to genetics, environmental factors also contribute to HS. For example, a retrospective study (n=45) demonstrated that ten patients had reported mechanical irritation before the disease started.…”

Section: Risk Factors or Determinants Of Hidradenitis Suppurativamentioning

confidence: 99%

Incidence, Risk Factors, and Prognosis of Hidradenitis Suppurativa Across the Globe: Insights from the Literature

Alotaibi¹

2023

CCID

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Hidradenitis suppurativa, a chronic inflammatory disease of the skin, affects a patient’s quality of life to a greater extent. While the disease burden, including its incidence and prevalence, has been extensively studied in the western population, there is a paucity of data from developing countries on the epidemiology of Hidradenitis suppurativa. Therefore, a general literature review was conducted to shed light on the epidemiology of Hidradenitis suppurativa across the globe. We reviewed the most recently available information on epidemiology, including incidence, prevalence, risk factors, prognosis and quality of life, complications, and associated comorbid among patients with Hidradenitis suppurativa. The estimated global prevalence of Hidradenitis suppurativa is found to be 0.00033–4.1%, with a relatively higher prevalence of 0.7–1.2% in European and US populations. Both genetic and environmental factors are associated with Hidradenitis suppurativa. Patients with Hidradenitis suppurativa have associated comorbid such as cardiovascular disease, type II diabetes mellitus, mental health issues, and sleep and sexual dysfunctions. These patients spend poor quality of life and tend to be less productive. Future studies are needed to assess the burden of Hidradenitis suppurativa in developing countries. Since the disease tends to be underdiagnosed, future studies should rely on clinical diagnosis rather than self-reporting to avoid the potential of recall bias. Attention needs to be diverted to developing countries with less amount of data on Hidradenitis suppurativa.

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“…This devastating disease has a significant impact on many aspects of patients’ lives [ 7 ]. The cause of hair follicle plugging is still unclear and subject to scientific debate, although immune and genetic factors, particularly variants in genes encoding ɣ secretase complex proteins ( NCSTN encoding nicastrin; PSEN1 for presenilin-1; PSENEN for presenilin enhancer; gamma-secretase subunit), hormonal fluctuations, and environmental risk factors are believed to play a role [ 8 , 9 , 10 ]. The most common sites for hidradenitis suppurativa are the main folds of the body, including the axillary and inguinal regions, the skin of the buttocks, the sub-mammary area, and the neck, waist, and inner side of the thighs [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Platelet-Rich Plasma and Acellular Dermal Matrix in the Surgical Treatment of Hidradenitis Suppurativa: A Comparative Retrospective Study

Gierek

Klama-Baryła

Łabuś

et al. 2023

JCM

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(1) Introduction: Hidradenitis suppurativa (HS) is an inflammatory skin disease with recurrent, chronic, painful, and purulent skin lesions. Topical or systemic antibiotics are the most widely used treatments for the management of mild stages of the disease. In chronic cases (Hurley II/III), wide excision of lesions should be considered. During reconstructive surgery, the most problematic aspect is wound closure. Very large excisional wounds require reconstructive techniques such as skin flaps, skin grafts, or both. Surgical methods have their limitations, so reconstructive methods in HS surgery need to be continuously improved through the use of, for example, platelet-rich plasma and acellular dermal matrix; (2) Methods: The aim of this study was to evaluate the clinical outcomes and efficacy of surgical treatment of patients with HS using local skin flaps injected with PRP compared to a group of local skin flaps without platelet-rich plasma injection, an acellular dermal matrix, and split-thickness skin graft co-grafts. Sixty-one patients (29 males and 32 females) were included in the study. Most patients were characterized by Hurley grade III HS; (3) Results: The use of PRP injection in reconstructions (skin flaps) improved healing and reduced the number of complications, a notable trend in this study. A co-graft of acellular dermal matrix and split-thickness skin graft gave better therapeutic results than split-thickness skin graft alone (fewer days in hospital, fewer postoperative complications); (4) Conclusions: PRP injected into skin flaps, co-grafted acellular dermal matrix, and split-thickness skin grafts are good options for the surgical treatment of hidradenitis suppurativa.

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Interpreting the spectrum of gamma-secretase complex missense variation in the context of hidradenitis suppurativa—An in-silico study

Cited by 9 publications

References 82 publications

NCSTN In-Frame Deletion in Maltese Patients With Hidradenitis Suppurativa

NCSTN In-Frame Deletion in Maltese Patients With Hidradenitis Suppurativa

Incidence, Risk Factors, and Prognosis of Hidradenitis Suppurativa Across the Globe: Insights from the Literature

Platelet-Rich Plasma and Acellular Dermal Matrix in the Surgical Treatment of Hidradenitis Suppurativa: A Comparative Retrospective Study

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