Highlights
- •Whole Exome Sequencing approach and novel bioinformatic pipeline has been adopted.
- •4 biological pathways are shared by all PASH and PAPASH patients.
- •All pathways are related to biological processes involving the skin.
- •The mainly impacted pathway is Vitamin D metabolism.
- •All patients show low Vitamin D serum levels and its supplementation is envisaged.
Abstract
Background
Diagnosis of pyoderma gangrenosum, acne and hidradenitis suppurativa (PASH) and pyogenic
arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH) patients,
in spite of recently identified genetic variations, is just clinical, since most patients
do not share the same mutations, and the mutations themselves are not informative
of the biological pathways commonly disrupted in these patients.
Objective
To reveal genetic changes more closely related to PASH and PAPASH etiopathogenesis,
identifying novel common pathways involved in these diseases.
Methods
Cohort study on PASH (n = 4) and PAPASH (n = 1) patients conducted using whole exome sequencing (WES) approach and a novel bioinformatic
pipeline aimed at discovering potentially candidate genes selected from density mutations
and involved in pathways relevant to the disease.
Results
WES results showed that patients presented 90 genes carrying mutations with deleterious
and/or damage impact: 12 genes were in common among the 5 patients and bared 237 ns
ExonVar (54 and 183 in homozygosis and heterozygosis, respectively). In the pathway
enrichment analysis, only 10 genes were included, allowing us to retrieve 4 pathways
shared by all patients: (1) Vitamin D metabolism, (2) keratinization, (3) formation
of the cornified envelope and (4) steroid metabolism. Interestingly, all patients
had vitamin D levels lower than normal, with a mean value of 10 ng/mL.
Conclusion
Our findings, through a novel strategy for analysing the genetic background of syndromic
HS patients, suggested that vitamin D metabolism dysfunctions seem to be crucial in
PASH and PAPASH pathogenesis. Based on low vitamin D serum levels, its supplementation
is envisaged.
Abbreviations:
PASH (pyoderma gangrenosum acne and hidradenitis suppurativa), PAPASH (pyoderma gangrenosum acne, pyogenic arthritis and hidradenitis suppurativa), HS (hidradenitis suppurativa), WES (whole exome sequencing), PG (pyoderma gangrenosum), PASS (pyoderma gangrenosum acne vulgaris, hidradenitis suppurativa and ankylosing spondylitis), IHS4 (International Hidradenitis Suppurativa Severity Score System), DLQI (dermatology life quality index), VAS (visual analogue scale), VDR (vitamin D receptor), DAMPs (damage-associated molecular patterns), ECM (extracellular matrix), MMPss (matrix metalloproteinases)Keywords
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Article info
Publication history
Published online: May 21, 2020
Accepted:
May 1,
2020
Received in revised form:
April 10,
2020
Received:
January 14,
2020
Identification
Copyright
© 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
