Long‐range genomic regulators of <i>THBS1</i> and <i>LTBP4</i> modify disease severity in duchenne muscular dystrophy

Weiss, Robert B.; Vieland, Veronica J.; Dunn, Diane M.; Kaminoh, Yuuki; Flanigan, Kevin M.

doi:10.1002/ana.25283

Cited by 49 publications

(75 citation statements)

References 49 publications

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“…We acknowledge several limitations to this study: the retrospective nature of Italian cohort data, compensated for by the longitudinal CINRG‐DNHS 4 ; the fact that variability in the Italian data may be affected by changes in practice during the long time frame of data collection; the unavailability of maximal inspiratory and expiratory pressure (MIP and MEP) data, which we plan to collect in future studies; the concern that missing NIV data adds uncertainty to corresponding conclusions; and finally, lack of genotyping, because of limited DNA availability, at a THBS1 long‐range genomic regulator locus recently added to the list of DMD modifiers 41 …”

Section: Discussionmentioning

confidence: 99%

Genetic modifiers of respiratory function in Duchenne muscular dystrophy

Bello

D'Angelo

Villa

et al. 2020

Ann Clin Transl Neurol

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Objective: Respiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). Methods and Results: Generalized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow-up time of 4.5 years, 786 estimated that forced vital capacity (FVC) declined yearly by À4.2%, forced expiratory volume in 1 sec by À5.0%, and peak expiratory flow (PEF) by À2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately + 15% across disease stages). Mutations situated 3' of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately À6%) PFT values, a finding independently validated in the CINRG-DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta-analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF. Interpretation: These findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.

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Section: Discussionmentioning

confidence: 99%

Genetic modifiers of respiratory function in Duchenne muscular dystrophy

Bello

D'Angelo

Villa

et al. 2020

Ann Clin Transl Neurol

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“…Using this categorisation we were able to segregate patients belonging to different categories. Published estimates for loss of ambulation consistently report a mean age of 10 [22,24,37]. The most recent report showed a mean of 10.6 with standard deviation [SD] = 2.3 [24].…”

Section: Discussionmentioning

confidence: 99%

TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy

Spitali

Zaharieva²,

Böhringer

et al. 2020

Eur J Hum Genet

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Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the DMD gene leading to the lack of dystrophin. Variability in the disease course suggests that other factors influence disease progression. With this study we aimed to identify genetic factors that may account for some of the variability in the clinical presentation. We compared whole-exome sequencing (WES) data in 27 DMD patients with extreme phenotypes to identify candidate variants that could affect disease progression. Validation of the candidate SNPs was performed in two independent cohorts including 301 (BIO-NMD cohort) and 109 (CINRG cohort of European ancestry) DMD patients, respectively. Variants in the Tctex1 domain containing 1 (TCTEX1D1) gene on chromosome 1 were associated with age of ambulation loss. The minor alleles of two independent variants, known to affect TCTEX1D1 coding sequence and induce skipping of its exon 4, were associated with earlier loss of ambulation. Our data show that disease progression of DMD is affected by a new locus on chromosome 1 and demonstrate the possibility to identify genetic modifiers in rare diseases by studying WES data in patients with extreme phenotypes followed by multiple layers of validation.

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“…Only a few papers report on SNPs associated with DMD. Among these, SPP1 and LTBP4 are validated genetic modifiers linked to LoA in steroid-treated boys (Flanigan et al, 2013;Bello et al, 2015;van den Bergen et al, 2015), while promising new biomarkers, as ACTN3 and CD40, or THBS1 as locus modifier, were recently identified as associated with LoA in DMD boys (Bello et al, 2016;Hogarth et al, 2017;Weiss et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy

et al. 2020

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Background: Duchenne muscular dystrophy (DMD) is a rare and severe X-linked muscular dystrophy in which the standard of care with variable outcome, also due to different drug response, is chronic off-label treatment with corticosteroids (CS). In order to search for SNP biomarkers for corticosteroid responsiveness, we genotyped variants across 205 DMD-related genes in patients with differential response to steroid treatment. Methods and Findings: We enrolled a total of 228 DMD patients with identified dystrophin mutations, 78 of these patients have been under corticosteroid treatment for at least 5 years. DMD patients were defined as high responders (HR) if they had

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Long‐range genomic regulators of THBS1 and LTBP4 modify disease severity in duchenne muscular dystrophy

Abstract: Together with previous evidence implicating LTBP4, the THBS1 modifier locus emphasizes the role that common regulatory variants in gene interaction networks can play in mitigating disease progression in muscular dystrophy. Ann Neurol 2018;84:234-245.

Cited by 49 publications

References 49 publications

Genetic modifiers of respiratory function in Duchenne muscular dystrophy

Genetic modifiers of respiratory function in Duchenne muscular dystrophy

TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy

Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy

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