Líffræðifélag Íslands - biologia.is
Líffræðiráðstefnan 2023
Höfundar / Authors: Brynja Matthiasardottir (1,2), Sarah Blackstone (1), Stephen M. Mount (2), Kathryn S. Torok (3), Daniel L. Kastner (1)
Starfsvettvangur / Affiliations: 1) National Institutes of Health, 2) University of Maryland, 3) University of Pittsburgh
Kynnir / Presenter: Brynja Matthiasardottir
Pediatric scleroderma is a rare disorder characterized by inflammation and fibrosis. It has two main forms, systemic sclerosis (SSc) and localized scleroderma (LS), both defined by excessive collagen deposition, but with different clinical manifestations and severity. GWAS has identified some associations, however, the etiology of this disease and the role of genomics is largely unknown. Most cases are sporadic, and this disease is generally not considered to be monogenic. Given the young onset and severity, we hypothesized that cases of pediatric scleroderma could be caused by highly penetrant pathogenic variants.
Exome and targeted sequencing were performed on 550 participants. Sequencing revealed 98 candidate variants by an optimized variant impact prediction approach. This included three heterozygous missense gain-of-function variants in STAT4, one of which did not meet conventional pathogenicity prediction criteria. We showed that these variants in STAT4 cause disabling pansclerotic morphea (DPM), a severe form of LS with a previously unknown etiology and high mortality. Our findings identify DPM as a novel autoinflammatory disorder and identify therapeutic targets that may not have been considered previously for scleroderma. The JAK inhibitor ruxolitinib attenuated the phenotype in vitro and in patients. Functional evaluation on other candidate variants detected in novel genes is under way, with preliminary findings highlighting the JAK/STAT pathway in scleroderma.