The TREAT-NMD DMD Global Database: Analysis of More than 7,000 Duchenne Muscular Dystrophy Mutations

Abstract

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).

Disease-proportional proteasomal degradation of missense dystrophins

“…The types of mutations causing DMD and BMD include insertions, deletions, point mutations, and splice site mutations (12). A recent collaborative data bank has calculated that patients with nonsense mutations account for ∼10% of dystrophinopathies (13), all of whom are the target population for stop codon read-through therapies (14). Patients with small insertions or deletions (indels) represent ∼7% of the total DMD/ BMD population (13).…”

“…A recent collaborative data bank has calculated that patients with nonsense mutations account for ∼10% of dystrophinopathies (13), all of whom are the target population for stop codon read-through therapies (14). Patients with small insertions or deletions (indels) represent ∼7% of the total DMD/ BMD population (13). When indel mutations cause a frameshift, they can specifically be targeted by current exon-skipping strategies (15).…”

“…When indel mutations cause a frameshift, they can specifically be targeted by current exon-skipping strategies (15). Patients with missense mutations account for only a small percentage of dystrophinopathies (<1%) (13), yet they represent an orphaned subpopulation with an undetermined pathomechanism and no current personalized therapies.…”

Brazilian consensus on Duchenne muscular dystrophy. Part 1: diagnosis, steroid therapy and perspectives

“…Different types of mutations in DMD can be the genetic basis for the disease. The most common mutation types are large deletions and duplications followed by point mutation, small deletions or insertions and splice site mutations 16 . Therefore, first-line genetic testing for DMD should be a technique that evaluates copy number variation to detect large deletions of one or more exons and duplications.…”

“…If deletion/duplication testing is negative, then DMD sequencing should be done to look for point mutations or small deletions/insertions. The DMD is one of the largest human genes with 79 exons in total 16 , which makes conventional Sanger sequencing very difficult, laborious and expensive. Next-generation sequencing, which allows massive and parallel sequencing of DNA fragments can now be considered the test of choice for DMD sequencing (Level of evidence: 3B, Class of Recommendation: B) 23,24 .…”