title: A systematic review and critical evaluation of reported pathogenic sequence variants in hidradenitis suppurativa.
abstract: Hidradenitis suppurativa (HS) is a severe chronic inflammatory disorder characterized by recurrent painful deep-seated nodules with a predilection to the apocrine-bearing areas of skin. A minority of cases of HS are due to mutations in the γ-secretase complex. Contention exists surrounding the pathogenicity of sequence variants and their effects upon Notch signalling. This systematic review was registered with PROSPERO (CRD42016041425) and was conducted in line with the PRISMA statement. Eligibility criteria for this review included published case reports, case series and reviews that identified sequence variants or protein or functional studies from patients with HS. Sixty-two articles were identified reporting a total of 41 sequence variants - heterozygous missense (nine), splice site (nine), insertion resulting in frameshift (one), premature termination codon (19) and promoter region PSTPIP1 (three) - with 18 associated protein or functional studies. The American College of Medical Genetics and Genomics standards and guidelines on the interpretation of sequence variants were applied to each identified variant to assess evidence for pathogenicity. Twenty-three variants were assessed as likely pathogenic, 17 of uncertain significance and one benign. The large number of variants of 'uncertain significance' is largely due to the variable number of functional studies. Four studies used Notch as a proxy for γ-secretase function, with conclusions of nonpathogenicity based on the assumption of Notch signalling as the sole pathogenic process. The role of Notch-independent signalling mechanisms requires further research. Limitations to this study include identification of variants of Mendelian inheritance and not complex polygenic traits.
authors.affiliation: Department of Dermatology, Liverpool Hospital, Sydney, New South Wales, Australia.|University of New South Wales, Sydney, New South Wales, Australia.|Ingham Institute of Applied Medical Research, Liverpool, New South Wales, Australia.
authors.forename: J W
authors.identifier: http://orcid.org/0000-0001-5042-3632
authors.initials: JW
authors.lastname: Frew
authors.affiliation: Department of Dermatology, Liverpool Hospital, Sydney, New South Wales, Australia.|University of New South Wales, Sydney, New South Wales, Australia.|Ingham Institute of Applied Medical Research, Liverpool, New South Wales, Australia.
authors.forename: D A
authors.initials: DA
authors.lastname: Vekic
authors.affiliation: Department of Dermatology, Liverpool Hospital, Sydney, New South Wales, Australia.|University of New South Wales, Sydney, New South Wales, Australia.|Ingham Institute of Applied Medical Research, Liverpool, New South Wales, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Woods
authors.affiliation: Department of Dermatology, Liverpool Hospital, Sydney, New South Wales, Australia.|University of New South Wales, Sydney, New South Wales, Australia.|Ingham Institute of Applied Medical Research, Liverpool, New South Wales, Australia.
authors.forename: G D
authors.initials: GD
authors.lastname: Cains
mesh_terms: D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006579:Heterozygote; D017497:Hidradenitis Suppurativa / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics
chemical_list: D022821:RNA Splice Sites; D051880:Receptors, Notch