1. Is it time for genetic modifiers to predict prognosis in Duchenne muscular dystrophy?
- Author
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Bello, Luca, Hoffman, Eric P., and Pegoraro, Elena
- Subjects
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DUCHENNE muscular dystrophy , *EXPERIMENTAL design , *FAMILY counseling , *PHENOTYPIC plasticity , *PROGNOSIS - Abstract
Patients with Duchenne muscular dystrophy (DMD) show clinically relevant phenotypic variability, despite sharing the same primary biochemical defect (dystrophin deficiency). Factors contributing to this clinical variability include allelic heterogeneity (specific DMD mutations), genetic modifiers (trans-acting genetic polymorphisms) and variations in clinical care. Recently, a series of genetic modifiers have been identified, mostly involving genes and/or proteins that regulate inflammation and fibrosis — processes increasingly recognized as being causally linked with physical disability. This article reviews genetic modifier studies in DMD to date and discusses the effect of genetic modifiers on predicting disease trajectories (prognosis), clinical trial design and interpretation (inclusion of genotype-stratified subgroup analyses) and therapeutic approaches. The genetic modifiers identified to date underscore the importance of progressive fibrosis, downstream of dystrophin deficiency, in driving the disease process. As such, genetic modifiers have shown the importance of therapies aimed at slowing this fibrotic process and might point to key drug targets. Patients with Duchenne muscular dystrophy show clinically relevant phenotypic variability, despite sharing the same primary biochemical defect (dystrophin deficiency). In this Review, the authors provide an overview of the current evidence on Duchenne muscular dystrophy genetic modifiers that contribute to this variability. Key points: Clinically relevant variability in disease severity and progression is observed in Duchenne muscular dystrophy (DMD) and can be explained by allelic heterogeneity within the DMD locus ('cis' modifiers) and polymorphisms in different loci ('trans' modifiers). Understanding the bases of clinical variability is important for patient and family counselling and prognosis, clinical trial design and the identification of therapeutic targets. The main identified modifiers influence inflammation and fibrotic replacement, highlighting the central role of these processes in DMD and the importance of addressing them pharmacologically. Modifier genes and proteins might become targets for therapeutic modulation themselves, predict responsiveness to treatments or enable precise subgroup analyses in clinical trials. Future developments in the field include the identification of novel modifiers by genome mapping in large, deeply phenotyped cohorts and the development of multilocus interaction models. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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