Objective: To describe the diagnostic yield of whole exome sequencing (WES) to identify autosomal dominant spinocerebellar ataxias (SCAs) caused by point mutations.

Background: There are currently 48 different subtypes of SCAs, and the most frequent are caused by expansions. SCAs caused by point mutations are unusual, but from the 48 subtypes described, the majority are caused by point mutations. Several studies have demonstrated the potential yield of WES to define the genetic etiology of unusual causes of undetermined ataxias. Thus, WES have a potential yield to define patients with undetermined ataxia or the genetic cause of undetermined SCAs, when expansions are ruled out.

Method: We performed WES in 119 patients with undetermined ataxias. Part of this sample, 12 cases, were comprised by undetermined SCAs (familial ataxia, and negative tests for most common SCAS caused by expansion: SCA1,2,3,6,7,10,12,17,DRPLA), and 107 cases were comprised by sporadic and adult onset undetermined ataxia, with no family history.

Results: We identified a total of 18 patients with SCAs associated with point mutations: 2 patients with SCA45 (FAT2), 3 patients with SCA5 (SPTBN2), 1 patient with SCA23 (PDYN), 3 patients with SCA28 (AFG3L2), 2 patients with SCA42 (CACNA1G), 1 patient with SCA26 (EEF2), 1 patient with SCA15 (ITPR1), 1 patient with SCA48 (STUB1), 3 patients with SCA14 (PRKCG), and 1 patient with SCA21 (TMEM240).

Conclusion: WES was diagnostic in 15,2% (18 from 119) of cases of the Brazilian cohort of undetermined ataxia cases in order to identify SCAs related to point mutations. The most common SCAs caused by point mutation identified in our series were SCA5, SCA14, SCA23, SCA28, SCA45 and SCA48. These results have implications for diagnosis, genetic counseling and eventually treatment.

References: Galatolo D, De Michele G, Silvestri G, Leuzzi V, Casali C, Musumeci O, Antenora A, Astrea G, Barghigiani M, Battini R, Battisti C, Caputi C, Cioffi E, De Michele G, Dotti MT, Fico T, Fiorillo C, Galosi S, Lieto M, Malandrini A, Melone MAB, Mignarri A, Natale G, Pegoraro E, Petrucci A, Ricca I, Riso V, Rossi S, Rubegni A, Scarlatti A, Tinelli F, Trovato R, Tedeschi G, Tessa A, Filla A, Santorelli FM. NGS in Hereditary Ataxia: When Rare Becomes Frequent. Int J Mol Sci. 2021 Aug 6;22(16):8490.

da Graça FF, Peluzzo TM, Bonadia LC, Martinez ARM, Diniz de Lima F, Pedroso JL, Barsottini OGP, Gama MTD, Akçimen F, Dion PA, Rouleau GA, Marques W Jr, França MC Jr. Diagnostic Yield of Whole Exome Sequencing for Adults with Ataxia: a Brazilian Perspective. Cerebellum. 2022 Feb;21(1):49-54.

This work was funded by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

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MDS Abstracts - https://www.mdsabstracts.org/abstract/diagnostic-yield-for-point-mutation-related-scas-through-exome-sequencing-for-undetermined-ataxias/