TY  - JOUR
UR  - https://doi.org/10.1093/braincomms/fcad244
A1  - Lam, Tanya
A1  - Rocca, Clarissa
A1  - Ibanez, Kristina
A1  - Dalmia, Anupriya
A1  - Tallman, Samuel
A1  - Hadjivassiliou, Marios
A1  - Hensiek, Anke
A1  - Nemeth, Andrea
A1  - Facchini, Stefano
A1  - Genomics England Research Consortium
A1  - Wood, Nicholas
A1  - Cortese, Andrea
A1  - Houlden, Henry
A1  - Tucci, Arianna
SN  - 2632-1297
JF  - Brain Communications
ID  - discovery10179125
Y1  - 2023///
KW  - NOP56
KW  -  SCA36
KW  -  repeat expansion
KW  -  spinocerebellar ataxia
KW  -  whole-genome sequencing
AV  - public
IS  - 5
VL  - 5
N2  - Spinocerebellar ataxias form a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by progressive cerebellar ataxia. Their prevalence varies among populations and ethnicities. Spinocerebellar ataxia 36 is caused by a GGCCTG repeat expansion in the first intron of the NOP56 gene and is characterized by late-onset ataxia, sensorineural hearing loss and upper and lower motor neuron signs, including tongue fasciculations. Spinocerebellar ataxia 36 has been described mainly in East Asian and Western European patients and was thought to be absent in the British population. Leveraging novel bioinformatic tools to detect repeat expansions from whole-genome sequencing, we analyse the NOP56 repeat in 1257 British patients with hereditary ataxia and in 7506 unrelated controls. We identify pathogenic repeat expansions in five families (seven patients), representing the first cohort of White British descent patients with spinocerebellar ataxia 36. Employing in silico approaches using whole-genome sequencing data, we found an 87?kb shared haplotype in among the affected individuals from five families around the NOP56 repeat region, although this block was also shared between several controls, suggesting that the repeat arises on a permissive haplotype. Clinically, the patients presented with slowly progressive cerebellar ataxia with a low rate of hearing loss and variable rates of motor neuron impairment. Our findings show that the NOP56 expansion causes ataxia in the British population and that spinocerebellar ataxia 36 can be suspected in patients with a late-onset, slowly progressive ataxia, even without the findings of hearing loss and tongue fasciculation.
TI  - Repeat expansions in NOP56 are a cause of spinocerebellar ataxia Type 36 in the British population
N1  - © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
ER  -