Abstract
Objective Genetic diagnosis and mutation identification are now compulsory for Duchenne (DMD) and Becker muscular dystrophies (BMD), which are due to dystrophin (DMD) gene mutations, either for disease prevention or personalized therapies. To evaluate the ethnic-related genetic assortments of DMD mutations, which may impact on DMD genetic diagnosis pipelines, we studied 328 patients with DMD and BMD from non-European countries.
Methods We performed a full DMD mutation detection in 328 patients from 10 Eastern European countries (Poland, Hungary, Lithuania, Romania, Serbia, Croatia, Bosnia, Bulgaria, Ukraine, and Russia) and 2 non-European countries (Cyprus and Algeria). We used both conventional methods (multiplex ligation-dependent probe amplification [MLPA] followed by gene-specific sequencing) and whole-exome sequencing (WES) as a pivotal study ran in 28 patients where DMD mutations were already identified by standard techniques. WES output was also interrogated for DMD gene modifiers.
Results We identified DMD gene mutations in 222 male patients. We identified a remarkable allele heterogeneity among different populations with a mutation landscape often country specific. We also showed that WES is effective for picking up all DMD deletions and small mutations and its adoption could allow a detection rate close to 90% of all occurring mutations. Gene modifiers haplotypes were identified with some ethnic-specific configurations.
Conclusions Our data provide unreported mutation landscapes in different countries, suggesting that ethnicity may orient genetic diagnosis flowchart, which can be adjusted depending on the mutation type frequency, with impact in drug eligibility.
Glossary
- ACMG=
- American College of Medical Genetics and Genomics;
- BMD=
- Becker muscular dystrophy;
- CK=
- creatine kinase;
- DMD=
- Duchenne muscular dystrophy;
- IGV=
- Integrative Genomics Viewer;
- LGMD=
- limb-girdle muscular dystrophy;
- NGS=
- next-generation sequencing;
- OMIM=
- Online Mendelian Inheritance in Man;
- VUS=
- variant of uncertain/unknown significance;
- WES=
- whole-exome sequencing;
- WGS=
- whole-genome sequencing
Footnotes
Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by Consorzio Futuro in Ricerca.
- Received May 24, 2020.
- Accepted in final form October 21, 2020.
- © 2020 American Academy of Neurology
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