ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10

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

doi:10.1016/j.xhgg.2022.100137

ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10

HGG Adv. 2022 Aug 15;3(4):100137. doi: 10.1016/j.xhgg.2022.100137. eCollection 2022 Oct 13.

Authors

C Alejandra Morato Torres¹, Faria Zafar¹, Yu-Chih Tsai², Jocelyn Palafox Vazquez¹, Michael D Gallagher³, Ian McLaughlin², Karl Hong³, Jill Lai³, Joyce Lee³, Amanda Chirino-Perez⁴, Angel Omar Romero-Molina⁴, Francisco Torres⁵, Juan Fernandez-Ruiz⁴, Tetsuo Ashizawa⁶, Janet Ziegle², Francisco Javier Jiménez Gil⁷, Birgitt Schüle¹

Affiliations

¹ Department Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Pacific Biosciences of California, Inc., Menlo Park, CA 94025, USA.
³ Bionano Genomics, San Diego, CA 92121, USA.
⁴ Laboratorio de Neuropsicología, Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, CDMX 04510, Mexico.
⁵ Southern California Permanente Medical Group, Oxnard, CA 93036, USA.
⁶ Department Neurology, Houston Methodist Research Institute, Houston, TX 77030, USA.
⁷ Hospital San Javier S.A. de C.V., Guadalajara, Jalisco 44670, Mexico.

Abstract

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 850-4,500 repeats. It has been shown that the repeat composition can be a modifier of disease, e.g., seizures. Here, we describe a Mexican kindred in which we identified both pure (ATTCT)_n and mixed (ATTCT)_n-(ATTCC)_n expansions in the same family. We used amplification-free targeted sequencing and optical genome mapping to decipher the composition of these repeat expansions. We found a considerable degree of mosaicism of the repeat expansion. This mosaicism was confirmed in skin fibroblasts from individuals with ATXN10 expansions 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 in individuals 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 are critical for clinical practice and genetic counseling, as variations in the repeat can affect disease penetrance, symptoms, and disease trajectory.

Keywords: ATAXIN10; ATXN10; SCA10; amplification-free targeted sequencing; long-read sequencing; optical genome mapping; penetrance; spinocerebellar ataxia type 10.