Current understanding of skeletal muscle repeat expansion disorders

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• The human genome contains millions of short tandem repeats (STRs), also known as microsatellites.
• STRs are repetitive DNA sequences that are highly variable and play roles in gene regulation and phenotypic diversity.
• Expansion of certain STRs beyond a threshold size causes approximately 60 neurological diseases, including major muscle disorders like myotonic dystrophy and oculopharyngodistal myopathy (OPDM).

Purpose of the Study:

• To summarize current knowledge on the genetics and proposed disease mechanisms of skeletal muscle STR expansion disorders.
• To highlight the role of advanced genomic technologies in discovering and characterizing these disorders, particularly OPDM.
• To discuss the evolving understanding of phenotypic spectrums and pathomechanisms.

Main Methods:

• Review of current scientific literature on STR expansion disorders.
• Analysis of genetic and molecular mechanisms underlying these conditions.
• Discussion of the impact of advanced genomic technologies, such as unbiased sequencing approaches.

Main Results:

• Numerous STR expansion disorders are now recognized, with genetic testing available on a research basis.
• Advanced genomic technologies have enabled the discovery and characterization of new STR expansion disorders, including OPDM.
• The phenotypic spectrums of these disorders are expanding as new cases with varied presentations are identified.

Conclusions:

• Clinical testing for newly identified STR expansion disorders is not yet widely available and can be complicated by reduced penetrance.
• The pathomechanisms are not fully understood but involve evidence of RNA toxicity and polyGly toxicity.
• Further research is expected to identify additional STR expansions linked to skeletal muscle diseases, enhancing our understanding of their complex genetics and epigenetics.