C. Alejandra Morato Torres, Faria Zafar, Yu-Chih Tsai, Jocelyn Palafox Vazquez, Michael D. Gallagher, Ian McLaughlin, Karl Hong, Jill Lai, Joyce Lee, Amanda Chirino-Perez, Angel Omar Romero-Molina, Francisco Torres, Juan Fernandez-Ruiz, Tetsuo Ashizawa, Janet Ziegle, Francisco Javier Jiménez Gil, Birgitt Schüle.
Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by an expanded pentanucleotide repeat in the ATXN10 gene. This repeat expansion, when fully penetrant, has a size of 850 to 4500 repeats. It has been shown that the repeat composition can be a modifier of disease, e.g., seizures. Here, we describe a Hispanic kindred in which we identified both pure (ATTCT)n expansions and mixed (ATTCT)n-(ATTCC)n in the same family. We used No-Amp targeted sequencing and optical genome mapping to decipher the composition of these repeat expansions. We found a considerable degree of mosaicism in the repeat expansion. This mosaicism was confirmed in skin fibroblasts from ATXN10 carriers with RNAScope in situ hybridization. All affected family members with the mixed ATXN10 repeat expansion showed typical clinical signs of spinocerebellar ataxia and epilepsy. In contrast, individuals with the pure ATXN10 expansion present with Parkinson’s disease or are unaffected even more than 20 years older than the average age at onset for SCA10. Our findings suggest that the pure (ATTCT)n expansion is non-pathogenic while repeat interruptions, e.g., (ATTCC)n, are necessary to cause SCA10. This mechanism has been recently described for several other repeat expansions, including SCA31 (BEAN1), SCA37 (DAB1), and three loci for benign adult familial myoclonic epilepsy BAFME (SAMD12, TNRC6A, RAPGEF2). Therefore, long-read sequencing and optical genome mapping of the entire genomic structure of repeat expansions is critical for clinical practice, and genetic counseling as variations in the repeat can affect disease penetrance, symptoms, and disease trajectory.