A circulating biomarker of facioscapulohumeral muscular dystrophy clinical severity, valid in skeletal muscle and blood

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is incurable. DUX4 mis-expression is believed to underlie FSHD pathogenesis, alongside PAX7 target gene repression, yet clinical trials lack robust biomarkers of severity. FSHD entails fatty replacement of muscle, accelerated by inflammation, we thus performed RNA-sequencing on both an MRI guided inflamed (TIRM+) and non-inflamed (TIRM-) muscle biopsies from clinically-characterised FSHD patients, alongside peripheral blood mononucleated cells (PBMCs). PAX7 target gene repression in TIRM- muscle associates with severity. DUX4 target gene biomarkers associate with lower limb fat fraction and D4Z4 repeat length, but not severity. PAX7 target gene repression in muscle correlates with levels in matched PBMCs. A refined biomarker computed in PBMCs associates with severity in FSHD patients, and also validates as a classifier of severity in an independent set of 54 FSHD patient blood samples. In summary, we present a minimally-invasive, circulating, transcriptomic biomarker of FSHD clinical severity valid in muscle and blood.

Insights in Genetics of Common and Rare Diseases: 2022

“…The comprehension of the mechanisms underlying the complex molecular background of FSHD is an area of active research. On this subject, recent studies described transcriptomic and proteomic markers associated with FSHD clinical severity and progression in muscle and blood (Banerji et al, 2019;Corasolla Carregari et al, 2020;Wong et al, 2020;Banerji et al, 2022). In addition, several studies highlighted DNA hypomethylation as a hallmark of disease (Hartwerk et al, 2013;Gaillard et al, 2014;Huichalaf et al, 2014;Calandra et al, 2016;Haynes et al, 2018;Lemmers et al, 2019;Roche et al, 2019;Gould et al, 2021;Banerji et al, 2022;Caputo et al, 2022b;Erdmann et al, 2022;Hiramuki et al, 2022).…”

“…On this subject, recent studies described transcriptomic and proteomic markers associated with FSHD clinical severity and progression in muscle and blood (Banerji et al, 2019;Corasolla Carregari et al, 2020;Wong et al, 2020;Banerji et al, 2022). In addition, several studies highlighted DNA hypomethylation as a hallmark of disease (Hartwerk et al, 2013;Gaillard et al, 2014;Huichalaf et al, 2014;Calandra et al, 2016;Haynes et al, 2018;Lemmers et al, 2019;Roche et al, 2019;Gould et al, 2021;Banerji et al, 2022;Caputo et al, 2022b;Erdmann et al, 2022;Hiramuki et al, 2022). In this scenario, the identification of SMCHD1, DNMT3B and LRIF1 as causative or modifier genes in FSHD1 and FSHD2 laid the foundations for considering FSHD as a complex disease, in which multiple genes are likely to contribute to the disease heterogeneity and variability (Caputo et al, 2022a) To this regard, NGS approaches are the ideal tool to allow the S3).…”

Whole exome sequencing highlights rare variants in CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1 as associated with FSHD

“…The comprehension of the mechanisms underlying the complex molecular background of FSHD is an area of active research. On this subject, recent studies described transcriptomic and proteomic markers associated with FSHD clinical severity and progression in muscle and blood ( Banerji et al, 2019 ; Corasolla Carregari et al, 2020 ; Wong et al, 2020 ; Banerji et al, 2022 ). In addition, several studies highlighted DNA hypomethylation as a hallmark of disease ( Hartwerk et al, 2013 ; Gaillard et al, 2014 ; Huichalaf et al, 2014 ; Calandra et al, 2016 ; Haynes et al, 2018 ; Lemmers et al, 2019 ; Roche et al, 2019 ; Gould et al, 2021 ; Banerji et al, 2022 ; Caputo et al, 2022b ; Erdmann et al, 2022 ; Hiramuki et al, 2022 ).…”

“…On this subject, recent studies described transcriptomic and proteomic markers associated with FSHD clinical severity and progression in muscle and blood ( Banerji et al, 2019 ; Corasolla Carregari et al, 2020 ; Wong et al, 2020 ; Banerji et al, 2022 ). In addition, several studies highlighted DNA hypomethylation as a hallmark of disease ( Hartwerk et al, 2013 ; Gaillard et al, 2014 ; Huichalaf et al, 2014 ; Calandra et al, 2016 ; Haynes et al, 2018 ; Lemmers et al, 2019 ; Roche et al, 2019 ; Gould et al, 2021 ; Banerji et al, 2022 ; Caputo et al, 2022b ; Erdmann et al, 2022 ; Hiramuki et al, 2022 ). In this scenario, the identification of SMCHD1 , DNMT3B and LRIF1 as causative or modifier genes in FSHD1 and FSHD2 laid the foundations for considering FSHD as a complex disease, in which multiple genes are likely to contribute to the disease heterogeneity and variability ( Caputo et al, 2022a ) To this regard, NGS approaches are the ideal tool to allow the simultaneous investigation of known FSHD causing ( SMCHD1 , DNMT3B and LRIF1 ) and other potential candidate gene modifiers.…”