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

Abstract

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.

Fig. 1. Workflow of genetic biomarker identification in DMD patients with extreme phenotype.

a DMD patients with early loss of ambulation (before the age of 8.5 years) and late loss of ambulation (after 12 years). b DMD patients with late onset cardiomyopathy and patients with early onset of cardiomyopathy. WES whole-exome sequencing, LoA loss of ambulation, GT genotype, NS non-synonymous.

Fig. 2. Q–Q plot showing the results obtained in the BIO-NMD validation cohort.

The observed P values are lower compared with the expected ones showing an enrichment in the obtained distribution compared with the observed one.

Fig. 3. Kaplan–Meier curves showing the effect of SNPs in chromosome 1 on age of ambulation loss.

a The effect of rs1060575 in the BIO-NMD validation cohort. b The SNP effects in the CINRG validation cohort. Censored patients are indicated by a cross on the lines.