Journal Article

DZNE-2023-00711

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.

Cunha, P. ; Petit, E. ; Coutelier, M. ; Coarelli, G. ; Mariotti, C. ; Faber, J.DZNE* ; Van Gaalen, J. ; Damasio, J. ; Fleszar, Z.DZNE* ; Tosi, M. ; Rocca, C. ; De Michele, G. ; Minnerop, M. ; Ewenczyk, C. ; Santorelli, F. M. ; Heinzmann, A. ; Bird, T. ; Amprosi, M. ; Indelicato, E. ; Benussi, A. ; Charles, P. ; Stendel, C.DZNE* ; Romano, S. ; Scarlato, M. ; Le Ber, I. ; Bassi, M. T. ; Serrano, M. ; Schmitz-Hübsch, T. ; Doss, S. ; Van Velzen, G. A. J. ; Thomas, Q. ; Trabacca, A. ; Ortigoza-Escobar, J. D. ; D'Arrigo, S. ; Timmann, D. ; Pantaleoni, C. ; Martinuzzi, A. ; Besse-Pinot, E. ; Marsili, L. ; Cioffi, E. ; Nicita, F. ; Giorgetti, A. ; Moroni, I. ; Romaniello, R. ; Casali, C. ; Ponger, P. ; Casari, G. ; De Bot, S. T. ; Ristori, G. ; Blumkin, L. ; Borroni, B. ; Goizet, C. ; Marelli, C. ; Boesch, S. ; Anheim, M. ; Filla, A. ; Houlden, H. ; Bertini, E. ; Klopstock, T.DZNE* ; Synofzik, M.DZNE* ; Riant, F. ; Zanni, G. ; Magri, S. ; Di Bella, D. ; Nanetti, L. ; Sequeiros, J. ; Oliveira, J. ; Van de Warrenburg, B. ; Schöls, L.DZNE* ; Taroni, F. ; Brice, A. ; Durr, A.

2023
Elsevier New York, NY

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Please use a persistent id in citations: doi:10.1016/j.ajhg.2023.05.009

Abstract: Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated genetic groups that had fewer than 30 subjects, there were 756 subjects bearing single-nucleotide variants or deletions in one of seven genes: CACNA1A (239 subjects), PRKCG (175), AFG3L2 (101), ITPR1 (91), STUB1 (77), SPTBN2 (39), or KCNC3 (34). We compared age at onset, disease features, and progression by gene and variant. There were no features that reliably distinguished one of these SCAs from another, and several genes-CACNA1A, ITPR1, SPTBN2, and KCNC3-were associated with both adult-onset and infantile-onset forms of disease, which also differed in presentation. Nevertheless, progression was overall very slow, and STUB1-associated disease was the fastest. Several variants in CACNA1A showed particularly wide ranges in age at onset: one variant produced anything from infantile developmental delay to ataxia onset at 64 years of age within the same family. For CACNA1A, ITPR1, and SPTBN2, the type of variant and charge change on the protein greatly affected the phenotype, defying pathogenicity prediction algorithms. Even with next-generation sequencing, accurate diagnosis requires dialogue between the clinician and the geneticist.

Keyword(s): Humans (MeSH) ; Spinocerebellar Ataxias: genetics (MeSH) ; Spinocerebellar Ataxias: diagnosis (MeSH) ; Cerebellar Ataxia: genetics (MeSH) ; Phenotype (MeSH) ; Ataxia: genetics (MeSH) ; Genetic Testing (MeSH) ; ATPases Associated with Diverse Cellular Activities: genetics (MeSH) ; ATP-Dependent Proteases: genetics (MeSH) ; Ubiquitin-Protein Ligases: genetics (MeSH) ; Spinocerebellar Ataxia, SCA, CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3, onset ; Spinocerebellar Ataxia, SCA, CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3, onset ; Spinocerebellar Ataxia, SCA, CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3, onset ; Spinocerebellar Ataxia, SCA, CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3, onset ; AFG3L2 protein, human ; ATPases Associated with Diverse Cellular Activities ; ATP-Dependent Proteases ; STUB1 protein, human ; Ubiquitin-Protein Ligases

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Contributing Institute(s):

1. Patient Studies Bonn (Patient Studies Bonn)
2. Clinical Neurogenetics (AG Schöls)
3. Parkinson Genetics (AG Gasser)
4. Clinical Research (Munich) (Clinical Research (Munich))
5. Translational Neurodegeneration (AG Höglinger 1)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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