Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center

Abstract

Recent developments in molecular therapies for Duchenne muscular dystrophy (DMD) demand accurate genetic diagnosis, because therapies are mutation specific. The KUCG (Kobe University Clinical Genetics) database for DMD and Becker muscular dystrophy is a hospital-based database comprising 442 cases. Using a combination of complementary DNA (cDNA) and chromosome analysis in addition to conventional genomic DNA-based method, mutation detection was successfully accomplished in all cases, and the largest mutation database of Japanese dystrophinopathy was established. Among 442 cases, deletions and duplications encompassing one or more exons were identified in 270 (61%) and 38 (9%) cases, respectively. Nucleotide changes leading to nonsense mutations or disrupting a splice site were identified in 69 (16%) or 24 (5%) cases, respectively. Small deletion/insertion mutations were identified in 34 (8%) cases. Remarkably, two retrotransposon insertion events were also identified. Dystrophin cDNA analysis successfully revealed novel transcripts with a pseudoexon created by a single-nucleotide change deep within an intron in four cases. X-chromosome abnormalities were identified in two cases. The reading frame rule was upheld for 93% of deletion and 66% of duplication mutation cases. For the application of molecular therapies, induction of exon skipping was deemed the first priority for dystrophinopathy treatment. At one Japanese referral center, the hospital-based mutation database of the dystrophin gene was for the first time established with the highest levels of quality and patient's number.

Haplotype-based approach for noninvasive prenatal tests of Duchenne muscular dystrophy using cell-free fetal DNA in maternal plasma

“…[1][2][3] Approximately 70% of DMD cases are caused by deletions/duplications of one or more DMD exons, and 30% of cases have DMD point mutations or small insertions/deletions. 4 Deletions/duplications are the most common type of diseasecausing mutation of the DMD gene. The importance of prevention has been greatly emphasized because no curative therapy is currently available.…”

Clinical Utility Gene Card for: Becker muscular dystrophy

“…Approximately 5-10% of BMD cases are a result of point variants. The majority of these are small indels and splice site variants, and less commonly missense variants; however, they can also affect dystrophin function [11,12]. Intronic variants can also negatively influence splicing and lead to BMD.…”

“…In-frame deletions (60-70%) and duplications (5-10%) account for the majority of BMD cases [11]. Approximately 5-10% of BMD cases are a result of point variants.…”

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

“…The key tests done in muscle biopsy for DMD are immunohistochemistry and immunoblotting for dystrophin, which should be interpreted by an experienced neuromuscular pathologist (Level of evidence: 4, Class of Recommendation: C) 25 . Additionally, when variants without defined pathogenicity are found on the next-generation sequencing of DMD, confirmation of the DMD diagnosis by muscle biopsy with immunohistochemistry will also be required (Level of evidence: 5, Class of Recommendation: D, Expert opinion).…”