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000258998 0247_ $$2doi$$a10.1016/j.ajhg.2023.05.009
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000258998 041__ $$aEnglish
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000258998 1001_ $$aCunha, Paulina$$b0
000258998 245__ $$aExtreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.
000258998 260__ $$aNew York, NY$$bElsevier$$c2023
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000258998 520__ $$aAlthough 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.
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000258998 650_2 $$2MeSH$$aHumans
000258998 650_2 $$2MeSH$$aSpinocerebellar Ataxias: genetics
000258998 650_2 $$2MeSH$$aSpinocerebellar Ataxias: diagnosis
000258998 650_2 $$2MeSH$$aCerebellar Ataxia: genetics
000258998 650_2 $$2MeSH$$aPhenotype
000258998 650_2 $$2MeSH$$aAtaxia: genetics
000258998 650_2 $$2MeSH$$aGenetic Testing
000258998 650_2 $$2MeSH$$aATPases Associated with Diverse Cellular Activities: genetics
000258998 650_2 $$2MeSH$$aATP-Dependent Proteases: genetics
000258998 650_2 $$2MeSH$$aUbiquitin-Protein Ligases: genetics
000258998 650_7 $$2Other$$aSpinocerebellar Ataxia, SCA, CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3, onset
000258998 650_7 $$2Other$$aSpinocerebellar Ataxia, SCA, CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3, onset
000258998 650_7 $$2Other$$aSpinocerebellar Ataxia, SCA, CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3, onset
000258998 650_7 $$2Other$$aSpinocerebellar Ataxia, SCA, CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3, onset
000258998 650_7 $$0EC 3.4.24.-$$2NLM Chemicals$$aAFG3L2 protein, human
000258998 650_7 $$0EC 3.6.4.-$$2NLM Chemicals$$aATPases Associated with Diverse Cellular Activities
000258998 650_7 $$0EC 3.4.21.-$$2NLM Chemicals$$aATP-Dependent Proteases
000258998 650_7 $$0EC 2.3.2.27$$2NLM Chemicals$$aSTUB1 protein, human
000258998 650_7 $$0EC 2.3.2.27$$2NLM Chemicals$$aUbiquitin-Protein Ligases
000258998 7001_ $$aPetit, Emilien$$b1
000258998 7001_ $$aCoutelier, Marie$$b2
000258998 7001_ $$aCoarelli, Giulia$$b3
000258998 7001_ $$aMariotti, Caterina$$b4
000258998 7001_ $$0P:(DE-2719)2811327$$aFaber, Jennifer$$b5$$udzne
000258998 7001_ $$aVan Gaalen, Judith$$b6
000258998 7001_ $$aDamasio, Joana$$b7
000258998 7001_ $$0P:(DE-2719)9000074$$aFleszar, Zofia$$b8$$udzne
000258998 7001_ $$aTosi, Michele$$b9
000258998 7001_ $$aRocca, Clarissa$$b10
000258998 7001_ $$aDe Michele, Giovanna$$b11
000258998 7001_ $$aMinnerop, Martina$$b12
000258998 7001_ $$aEwenczyk, Claire$$b13
000258998 7001_ $$aSantorelli, Filippo M$$b14
000258998 7001_ $$aHeinzmann, Anna$$b15
000258998 7001_ $$aBird, Thomas$$b16
000258998 7001_ $$aAmprosi, Matthias$$b17
000258998 7001_ $$aIndelicato, Elisabetta$$b18
000258998 7001_ $$aBenussi, Alberto$$b19
000258998 7001_ $$aCharles, Perrine$$b20
000258998 7001_ $$0P:(DE-2719)2812141$$aStendel, Claudia$$b21$$udzne
000258998 7001_ $$aRomano, Silvia$$b22
000258998 7001_ $$aScarlato, Marina$$b23
000258998 7001_ $$aLe Ber, Isabelle$$b24
000258998 7001_ $$aBassi, Maria Teresa$$b25
000258998 7001_ $$aSerrano, Mercedes$$b26
000258998 7001_ $$0P:(DE-HGF)0$$aSchmitz-Hübsch, Tanja$$b27
000258998 7001_ $$aDoss, Sarah$$b28
000258998 7001_ $$aVan Velzen, Gijs A J$$b29
000258998 7001_ $$aThomas, Quentin$$b30
000258998 7001_ $$aTrabacca, Antonio$$b31
000258998 7001_ $$aOrtigoza-Escobar, Juan Dario$$b32
000258998 7001_ $$aD'Arrigo, Stefano$$b33
000258998 7001_ $$aTimmann, Dagmar$$b34
000258998 7001_ $$aPantaleoni, Chiara$$b35
000258998 7001_ $$aMartinuzzi, Andrea$$b36
000258998 7001_ $$aBesse-Pinot, Elsa$$b37
000258998 7001_ $$aMarsili, Luca$$b38
000258998 7001_ $$aCioffi, Ettore$$b39
000258998 7001_ $$aNicita, Francesco$$b40
000258998 7001_ $$aGiorgetti, Alejandro$$b41
000258998 7001_ $$aMoroni, Isabella$$b42
000258998 7001_ $$aRomaniello, Romina$$b43
000258998 7001_ $$aCasali, Carlo$$b44
000258998 7001_ $$aPonger, Penina$$b45
000258998 7001_ $$aCasari, Giorgio$$b46
000258998 7001_ $$aDe Bot, Susanne T$$b47
000258998 7001_ $$aRistori, Giovanni$$b48
000258998 7001_ $$aBlumkin, Lubov$$b49
000258998 7001_ $$aBorroni, Barbara$$b50
000258998 7001_ $$aGoizet, Cyril$$b51
000258998 7001_ $$aMarelli, Cecilia$$b52
000258998 7001_ $$aBoesch, Sylvia$$b53
000258998 7001_ $$aAnheim, Mathieu$$b54
000258998 7001_ $$aFilla, Alessandro$$b55
000258998 7001_ $$aHoulden, Henry$$b56
000258998 7001_ $$aBertini, Enrico$$b57
000258998 7001_ $$0P:(DE-2719)2810704$$aKlopstock, Thomas$$b58$$udzne
000258998 7001_ $$0P:(DE-2719)2811275$$aSynofzik, Matthis$$b59$$udzne
000258998 7001_ $$aRiant, Florence$$b60
000258998 7001_ $$aZanni, Ginevra$$b61
000258998 7001_ $$aMagri, Stefania$$b62
000258998 7001_ $$aDi Bella, Daniela$$b63
000258998 7001_ $$aNanetti, Lorenzo$$b64
000258998 7001_ $$aSequeiros, Jorge$$b65
000258998 7001_ $$aOliveira, Jorge$$b66
000258998 7001_ $$aVan de Warrenburg, Bart$$b67
000258998 7001_ $$0P:(DE-2719)2810795$$aSchöls, Ludger$$b68$$udzne
000258998 7001_ $$aTaroni, Franco$$b69
000258998 7001_ $$aBrice, Alexis$$b70
000258998 7001_ $$aDurr, Alexandra$$b71
000258998 773__ $$0PERI:(DE-600)1473813-2$$a10.1016/j.ajhg.2023.05.009$$gVol. 110, no. 7, p. 1098 - 1109$$n7$$p1098 - 1109$$tThe American journal of human genetics$$v110$$x0002-9297$$y2023
000258998 8564_ $$uhttps://www.sciencedirect.com/science/article/abs/pii/S0002929723001660
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