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@ARTICLE{Cunha:258998,
author = {Cunha, Paulina and Petit, Emilien and Coutelier, Marie and
Coarelli, Giulia and Mariotti, Caterina and Faber, Jennifer
and Van Gaalen, Judith and Damasio, Joana and Fleszar, Zofia
and Tosi, Michele and Rocca, Clarissa and De Michele,
Giovanna and Minnerop, Martina and Ewenczyk, Claire and
Santorelli, Filippo M and Heinzmann, Anna and Bird, Thomas
and Amprosi, Matthias and Indelicato, Elisabetta and
Benussi, Alberto and Charles, Perrine and Stendel, Claudia
and Romano, Silvia and Scarlato, Marina and Le Ber, Isabelle
and Bassi, Maria Teresa and Serrano, Mercedes and
Schmitz-Hübsch, Tanja and Doss, Sarah and Van Velzen, Gijs
A J and Thomas, Quentin and Trabacca, Antonio and
Ortigoza-Escobar, Juan Dario and D'Arrigo, Stefano and
Timmann, Dagmar and Pantaleoni, Chiara and Martinuzzi,
Andrea and Besse-Pinot, Elsa and Marsili, Luca and Cioffi,
Ettore and Nicita, Francesco and Giorgetti, Alejandro and
Moroni, Isabella and Romaniello, Romina and Casali, Carlo
and Ponger, Penina and Casari, Giorgio and De Bot, Susanne T
and Ristori, Giovanni and Blumkin, Lubov and Borroni,
Barbara and Goizet, Cyril and Marelli, Cecilia and Boesch,
Sylvia and Anheim, Mathieu and Filla, Alessandro and
Houlden, Henry and Bertini, Enrico and Klopstock, Thomas and
Synofzik, Matthis and Riant, Florence and Zanni, Ginevra and
Magri, Stefania and Di Bella, Daniela and Nanetti, Lorenzo
and Sequeiros, Jorge and Oliveira, Jorge and Van de
Warrenburg, Bart and Schöls, Ludger and Taroni, Franco and
Brice, Alexis and Durr, Alexandra},
title = {{E}xtreme phenotypic heterogeneity in non-expansion
spinocerebellar ataxias.},
journal = {The American journal of human genetics},
volume = {110},
number = {7},
issn = {0002-9297},
address = {New York, NY},
publisher = {Elsevier},
reportid = {DZNE-2023-00711},
pages = {1098 - 1109},
year = {2023},
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.},
keywords = {Humans / Spinocerebellar Ataxias: genetics /
Spinocerebellar Ataxias: diagnosis / Cerebellar Ataxia:
genetics / Phenotype / Ataxia: genetics / Genetic Testing /
ATPases Associated with Diverse Cellular Activities:
genetics / ATP-Dependent Proteases: genetics /
Ubiquitin-Protein Ligases: genetics / Spinocerebellar
Ataxia, SCA,
CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3,
onset (Other) / Spinocerebellar Ataxia, SCA,
CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3,
onset (Other) / Spinocerebellar Ataxia, SCA,
CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3,
onset (Other) / Spinocerebellar Ataxia, SCA,
CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3,
onset (Other) / AFG3L2 protein, human (NLM Chemicals) /
ATPases Associated with Diverse Cellular Activities (NLM
Chemicals) / ATP-Dependent Proteases (NLM Chemicals) / STUB1
protein, human (NLM Chemicals) / Ubiquitin-Protein Ligases
(NLM Chemicals)},
cin = {Patient Studies Bonn / AG Schöls / AG Gasser / Clinical
Research (Munich) / AG Höglinger 1},
ddc = {570},
cid = {I:(DE-2719)1011101 / I:(DE-2719)5000005 /
I:(DE-2719)1210000 / I:(DE-2719)1111015 /
I:(DE-2719)1110002},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pmc = {pmc:PMC10357418},
pubmed = {pmid:37301203},
doi = {10.1016/j.ajhg.2023.05.009},
url = {https://pub.dzne.de/record/258998},
}