Novel ATXN10 Repeat Motif Patterns in Peruvian Families Modify Disease Onset

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant neurodegenerative disorder.
• It is caused by intronic pentanucleotide repeat expansions in the ATXN10 gene.
• Specific repeat motifs, beyond length, may influence SCA10 disease characteristics like seizures and penetrance.

Purpose of the Study:

• To investigate ATXN10 repeat motif patterns in Peruvian SCA10 kindreds.
• To explore genotype-phenotype correlations, focusing on repeat motif composition.
• To evaluate the utility of long-read sequencing (LRS) and optical genome mapping for characterizing these expansions.

Main Methods:

• Utilized a novel multiplex 20-gene panel with Cas9-targeted, amplification-free long-read sequencing (LRS).
• Employed optical genome mapping for comprehensive analysis of ATXN10 repeat structures.
• Analyzed index cases from 6 multigenerational Peruvian SCA10 families.

Main Results:

• Detected ATXN10 repeat expansions ranging from 990 to 2,002 repeats (4.9-10 kb) across the 6 families.
• Identified 3 distinct mixed repeat motif patterns, including ratios of (ATTCT)n(ATTCC)n.
• Observed associations between these mixed motif patterns and variations in age at disease onset and anticipation.

Conclusions:

• The alternate ATTCC motif is prominent alongside the common ATTCT motif in SCA10.
• The ratio of ATTCC motifs within repeat patterns, rather than repeat length alone, may correlate with SCA10 disease onset.
• Clinical LRS workflows need adaptation to fully characterize large repeat expansions at the nucleotide level for improved SCA10 diagnosis and understanding.