A journey through genetic movement disorders caused by non-coding repeat expansions.

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Nucleotide repeat expansions are a significant genetic cause of neurological disorders, particularly movement disorders.
• While coding region variants are known, non-coding repeat expansions are increasingly implicated in movement disorder pathogenesis.
• Recent discoveries link genes like FGF14, RFC1, and GLS to novel non-coding repeat expansion disorders.

Purpose of the Study:

• To review the genotypic and phenotypic characteristics of movement disorders caused by non-coding repeat expansions.
• To highlight recently identified genes associated with these conditions.
• To propose improved diagnostic strategies for clinical practice.

Main Methods:

• Narrative review of current literature on non-coding repeat expansion disorders.
• Analysis of genotypic and phenotypic data from identified cases.
• Discussion of diagnostic methodologies and limitations of standard genetic testing.

Main Results:

• Several new genes (FGF14, RFC1, GLS, NUTM2B-AS1, NOTCH2NLC, GIPC1) have been identified with non-coding repeat expansions causing movement disorders.
• Conventional short-read sequencing often misses these pathogenic expansions.
• Specialized techniques like repeat-primed PCR, Southern blotting, and long-read sequencing are necessary for detection.

Conclusions:

• Accurate diagnosis of non-coding repeat expansion movement disorders necessitates specialized genetic testing beyond standard panels.
• A phenotype-guided, targeted genetic testing approach can enhance diagnostic yield.
• Increased physician awareness of these disorders is vital for timely and correct diagnosis.