#apaperaday: Spectrum of Genetic Variants in the Dystrophin Gene: A Single Centre Retrospective Analysis of 750 Duchenne and Becker Patients from Southern Italy
In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Spectrum of Genetic Variants in the Dystrophin Gene: A Single Centre Retrospective Analysis of 750 Duchenne and Becker Patients from Southern Italy
Today’s pick is from the journal Genes by Viggiano et al on the spectrum of genetic variants in the dystrophin gene in dystrophinopathy patients from South Italy born between 1930 and 2020. DOI: 10.3390/genes14010214.
Dystrophinopathies are caused by variants in the DMD gene that encodes dystrophin. When variants prevent production of functional dystrophin (out of frame) they are associated with the severely progressive Duchenne muscular dystrophy.
When variants allow production of partially functional dystrophins (in-frame) they are associated with later onset and milder progressive Becker muscular dystrophy. Variants at the start of the gene can also cause X-linked cardiomyopathy, heart problems without muscle symptoms.
Authors make a number of points:
- Duchenne is named after Dr Duchenne describing the disease in 1868, Dr Conte already described 2 Italian patients in 1836
- Becker is milder compared to Duchenne, but still a severe disease, with 50% of patients having symptoms at age 12.
- Female carriers can have symptoms as well and are at risk of developing cardiomyopathy (~17% after age 40).
Authors outline current standards of care and treatment with steroids and outline that mutation specific approaches to restore dystrophin are approved in some regions. Furthermore, additional trials are ongoing for exon skipping approaches (approved in USA) and for microdystrophin gene therapy (not approved anywhere yet). Ataluren is approved in Europe.
Here authors describe their cohort of >700 patients diagnosed from 1990 to now, with dates of births from 1930-2020. They started with southern blot and PCR (detecting mostly deletions and with difficulty duplications) and later used MLPA and in 2014 also NGS for small mutations.
Pathogenic variants were found in 96% of patients, with 467 Duchenne and 252 Becker patients. 71% had a deletion, 10% a duplication and 15% a small mutation. Most deletions occurred between exon 45-55 and most deletions between exon 2-23 (in lines with other reports).
Point mutations were only found for patients born after 1971 and beyond (see image). This is not because they did not occur before, but because they were not looked for (not possible with techniques used then).
Authors stress a genetic diagnosis is important as it allows starting with care, offering counseling and assessing if mutation specific treatments apply. In Italy first contact (average) with the medical system due to symptoms is at 31 months, while genetic diagnosis is at 41 months.
Authors notice a reduction in patients born with Duchenne and Becker over time, likely due to genetic counseling. They stress that patients will always be born, due to the high rate of de novo mutations in germ cells.
They looked at distribution of mutation types in different reports, seeing that point mutations are often overestimated. They argue that most likely these more difficult to detect variants are enriched at expert centers, due to referral when deletions/duplications were not found.
Furthermore in other reports deletions and duplications are over reported, because authors do not have tools to identify small mutations. They see more patients are reported in Asia and Europe than North America, perhaps due to less access to genetic diagnosis (insurance). I like the way the authors give a reflective report of their own history of mutation analysis and how they put things in a global context as well.