TY  - JOUR
AU  - Cunha, Paulina
AU  - Petit, Emilien
AU  - Coutelier, Marie
AU  - Coarelli, Giulia
AU  - Mariotti, Caterina
AU  - Faber, Jennifer
AU  - Van Gaalen, Judith
AU  - Damasio, Joana
AU  - Fleszar, Zofia
AU  - Tosi, Michele
AU  - Rocca, Clarissa
AU  - De Michele, Giovanna
AU  - Minnerop, Martina
AU  - Ewenczyk, Claire
AU  - Santorelli, Filippo M
AU  - Heinzmann, Anna
AU  - Bird, Thomas
AU  - Amprosi, Matthias
AU  - Indelicato, Elisabetta
AU  - Benussi, Alberto
AU  - Charles, Perrine
AU  - Stendel, Claudia
AU  - Romano, Silvia
AU  - Scarlato, Marina
AU  - Le Ber, Isabelle
AU  - Bassi, Maria Teresa
AU  - Serrano, Mercedes
AU  - Schmitz-Hübsch, Tanja
AU  - Doss, Sarah
AU  - Van Velzen, Gijs A J
AU  - Thomas, Quentin
AU  - Trabacca, Antonio
AU  - Ortigoza-Escobar, Juan Dario
AU  - D'Arrigo, Stefano
AU  - Timmann, Dagmar
AU  - Pantaleoni, Chiara
AU  - Martinuzzi, Andrea
AU  - Besse-Pinot, Elsa
AU  - Marsili, Luca
AU  - Cioffi, Ettore
AU  - Nicita, Francesco
AU  - Giorgetti, Alejandro
AU  - Moroni, Isabella
AU  - Romaniello, Romina
AU  - Casali, Carlo
AU  - Ponger, Penina
AU  - Casari, Giorgio
AU  - De Bot, Susanne T
AU  - Ristori, Giovanni
AU  - Blumkin, Lubov
AU  - Borroni, Barbara
AU  - Goizet, Cyril
AU  - Marelli, Cecilia
AU  - Boesch, Sylvia
AU  - Anheim, Mathieu
AU  - Filla, Alessandro
AU  - Houlden, Henry
AU  - Bertini, Enrico
AU  - Klopstock, Thomas
AU  - Synofzik, Matthis
AU  - Riant, Florence
AU  - Zanni, Ginevra
AU  - Magri, Stefania
AU  - Di Bella, Daniela
AU  - Nanetti, Lorenzo
AU  - Sequeiros, Jorge
AU  - Oliveira, Jorge
AU  - Van de Warrenburg, Bart
AU  - Schöls, Ludger
AU  - Taroni, Franco
AU  - Brice, Alexis
AU  - Durr, Alexandra
TI  - Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.
JO  - The American journal of human genetics
VL  - 110
IS  - 7
SN  - 0002-9297
CY  - New York, NY
PB  - Elsevier
M1  - DZNE-2023-00711
SP  - 1098 - 1109
PY  - 2023
AB  - 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.
KW  - Humans
KW  - Spinocerebellar Ataxias: genetics
KW  - Spinocerebellar Ataxias: diagnosis
KW  - Cerebellar Ataxia: genetics
KW  - Phenotype
KW  - Ataxia: genetics
KW  - Genetic Testing
KW  - ATPases Associated with Diverse Cellular Activities: genetics
KW  - ATP-Dependent Proteases: genetics
KW  - Ubiquitin-Protein Ligases: genetics
KW  - Spinocerebellar Ataxia, SCA, CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3, onset (Other)
KW  - Spinocerebellar Ataxia, SCA, CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3, onset (Other)
KW  - Spinocerebellar Ataxia, SCA, CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3, onset (Other)
KW  - Spinocerebellar Ataxia, SCA, CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3, onset (Other)
KW  - AFG3L2 protein, human (NLM Chemicals)
KW  - ATPases Associated with Diverse Cellular Activities (NLM Chemicals)
KW  - ATP-Dependent Proteases (NLM Chemicals)
KW  - STUB1 protein, human (NLM Chemicals)
KW  - Ubiquitin-Protein Ligases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC10357418
C6  - pmid:37301203
DO  - DOI:10.1016/j.ajhg.2023.05.009
UR  - https://pub.dzne.de/record/258998
ER  -