Massey Sean, Guo Yiran, Riley Lisa G, Van Bergen Nicole J, Sandaradura Sarah A, McCusker Elizabeth, Tchan Michel, Thauvin-Robinet Christel, Thomas Quentin, Moreau Thibault, Davis Mark, Smits Daphne, Mancini Grazia M S, Hakonarson Hakon, Cooper Sandra, Christodoulou John
Brain and Mitochondrial Research Group (S.M., N.J.V.B., J.C.), Murdoch Children's Research Institute, Melbourne, VIC, Australia; Centre for Applied Genomics (Y.G., H.H.), Children's Hospital of Philadelphia, PA; Centre for Data Driven Discovery in Biomedicine (Y.G.), Children's Hospital of Philadelphia, PA; Rare Diseases Functional Genomics (L.G.R., S.C.), Kids Research, The Children's Hospital at Westmead and Children's Medical Research Institute, Sydney, NSW, Australia; Specialty of Child and Adolescent Health (L.G.R., S.C.), University of Sydney, NSW, Australia; Department of Paediatrics (N.J.V.B., J.C.), University of Melbourne, VIC, Australia; Department of Paediatrics and Child Health (S.A.S.), University of Sydney, NSW, Australia; Department of Clinical Genetics (S.A.S.), The Children's Hospital at Westmead, Sydney, NSW, Australia; Department of Genetic Medicine (M.T.), Westmead Hospital, Sydney, NSW, Australia; Department of Neurology (E.M.), Westmead Hospital, Sydney (NSW), Australia; Laboratory of Diagnostic Innovation in Rare Diseases (C.T.-R.), CHU Dijon Bourgogne, France; Genetics Center (C.T.-R.), CHU Dijon Bourgogne, France; Neurology (Q.T., T.M.), CHU Dijon Bourgogne, France; Diagnostics Genomics (M.D.), PathWest Laboratory Medicine, Perth, WA, Australia; and Department of Clinical Genetics (D.S., G.M.S.M.), ErasmusMC University Medical Center, Rotterdam, ZH, the Netherlands.
Neurol Genet. 2023 Jan 23;9(1):e200051. doi: 10.1212/NXG.0000000000200051. eCollection 2023 Feb.
The term autosomal recessive cerebellar ataxia (ARCA) encompasses a diverse group of heterogeneous degenerative disorders of the cerebellum. Spinocerebellar ataxia autosomal recessive 10 (SCAR10) is a distinct classification of cerebellar ataxia caused by variants in the gene. Little is known about the molecular role of ANO10 or its role in disease. There is a wide phenotypic spectrum among patients, even among those with the same or similar genetic variants. This study aimed to characterize the molecular consequences of variants in and determine their pathologic significance in patients diagnosed with SCAR10.
We presented 4 patients from 4 families diagnosed with spinocerebellar ataxia with potential pathogenic variants in the gene. Patients underwent either clinical whole-exome sequencing or screening of a panel of known neuromuscular disease genes. Effects on splicing were studied using reverse transcriptase PCR to analyze complementary DNA. Western blots were used to examine protein expression.
One individual who presented clinically at a much earlier age than typical was homozygous for an variant (c.1864A > G [p.Met622Val]) that produces 2 transcription products by altering an exonic enhancer site. Two patients, both of Lebanese descent, had a homozygous intronic splicing variant in (c.1163-9A > G) that introduced a cryptic splice site acceptor, producing 2 alternative transcription products and no detectable wild-type protein. Both these variants have not yet been associated with SCAR10. The remaining patient was found to have compound heterozygous variants in previously associated with SCAR10 (c.132dupA [p.Asp45Argfs*9] and c.1537T > C [p.Cys513Arg]).
We presented rare pathogenic variants adding to the growing list of variants associated with SCAR10. In addition, we described an individual with a much earlier age at onset than usually associated with variants. This expands the phenotypic and allelic heterogeneity of -associated ARCA.
常染色体隐性遗传性小脑共济失调（ARCA）一词涵盖了一组多样的小脑异质性退行性疾病。脊髓小脑共济失调常染色体隐性10型（SCAR10）是由该基因变异引起的一种独特的小脑共济失调分类。关于ANO10的分子作用或其在疾病中的作用知之甚少。患者之间存在广泛的表型谱，即使是那些具有相同或相似基因变异的患者也是如此。本研究旨在表征该基因变异的分子后果，并确定其在诊断为SCAR10的患者中的病理意义。
我们介绍了来自4个家庭的4例被诊断为脊髓小脑共济失调且该基因存在潜在致病变异的患者。患者接受了临床全外显子测序或一组已知神经肌肉疾病基因的筛查。使用逆转录聚合酶链反应分析互补DNA来研究对剪接的影响。蛋白质印迹法用于检测蛋白质表达。
一名临床发病年龄比典型情况早得多的个体为一个变异（c.1864A>G [p.Met622Val]）的纯合子，该变异通过改变一个外显子增强子位点产生2种转录产物。两名黎巴嫩裔患者在该基因中有一个纯合子内含子剪接变异（c.1163-9A>G），该变异引入了一个隐蔽的剪接受体位点，产生2种替代转录产物且未检测到野生型蛋白。这两种变异均尚未与SCAR10相关联。其余患者被发现该基因存在先前与SCAR10相关的复合杂合变异（c.132dupA [p.Asp45Argfs*9]和c.1537T>C [p.Cys513Arg]）。
我们展示了罕见的致病变异，增加了与SCAR10相关的该基因变异的列表。此外，我们描述了一名发病年龄比通常与该基因变异相关的情况早得多的个体。这扩展了与该基因相关的ARCA的表型和等位基因异质性。
