A systematic review and critical evaluation of reported sequence variants in hidradenitis suppurativa/acne inversa using ACMG standards and guidelines

Introduction: Hidradenitis Suppurativa / Acne Inversa (HS/AI) is a severe chronic inflammatory disorder characterised by recurrent painful deep seated nodules with a predilection to the apocrine bearing areas of skin. A minority of cases of HS/AI are due to mutations in the gamma secretase complex. Contention exists surrounding the pathogenicity of sequence variants.
Methods: 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 which identified sequence variants or protein/functional studies from patients with HS/AI.
Results: 62 articles reporting a total of 41 sequence variants (heterozygous missense (9), splice site (9), insertion resulting in frameshift (1) Premature Termination Codons (19), promoter region PSTPIP1 (3)) with 18 associated protein/functional studies. The American College of Medical Genetics (ACMG) standards and guidelines on the interpretation of sequence variants were applied to each identified variant to assess evidence for pathogenicity. 23 variants were assessed as likely pathogenic, 17 were of uncertain significance and 1 benign.
Discussion and Conclusions: The large number of variants of ‘uncertain significance’ is due to the variable number of functional studies. Four studies used Notch as a proxy for gamma secretase function with conclusions of non-pathogenicity based upon 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.

Dr. John Frew