DUCHENNE MUSCULAR DYSTROPHY - GENETICS: P.212Mutational spectrum of the DMD gene in pediatric patients from an Argentinian referral center

Abstract

Dystrophinopathies are a group of X-linked recessive neuromuscular disorders caused by mutations in DMD gene, which include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, X-linked dilated cardiomyopathy and mild forms of the disease. Large deletions and duplications account for 70% of the mutations while small mutations are found in the remaining 30% of the patients. Molecular diagnosis is important since it has implications in disease prognosis, genetic counselling and treatment options. In this study, we describe the mutation spectrum in DMD gene in patients from a Paediatric Reference Hospital in Argentina. A total of 344 unrelated patients (336 males/8 females) were studied by MLPA technique. Sequencing of DMD gene by Sanger or next generation sequencing was performed in 66 patients with negative MLPA, clinical and muscle biopsy compatible with dystrophinopathies. Molecular diagnosis was achieved in 276 (80.23%) of the cases. Overall, large deletions were found in 178 (65%) of the patients with positive results, followed by point mutations (22%) and large duplications (11%). Six patients showed contiguous gene deletion (2%). Point mutations identified in 62 patients were distributed as follows: 28 nonsense mutations, 19 small out of frame deletions, 8 splice site mutations, 3 small out of frame duplications, 2 missense mutations, 1 in frame deletion and 1 insertion. Genotype-phenotype analysis revealed exceptions to the reading frame rule in 10.1% of the cases. The highest percentage of this exception was due to in frame mutations that result in DMD phenotype caused by mutations that encompassed the actin binding domain and part of the rod domain. In conclusion, the diagnostic algorithm used in the present study was accurate for the molecular diagnosis of dystrophinopathies; in addition, this study provides data about phenotype characteristics and genetic profile in paediatric patients in our country.