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在非扩张的脊髓小脑缩症中极端的表型异质性

Paulina Cunha¹, Emilien Petit¹, Marie Coutelier¹

¹Sorbonne Université, Paris Brain Institute (ICM), Pitié-Salpêtrière Hospital, AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, CS21414, 75646 PARIS Cedex 13, France.

American journal of human genetics

|June 10, 2023

概括

许多脊髓小脑缩症 (SCAs) 并不是由重复扩张引起的. 基因型-表型相关性是复杂的,变异型和蛋白质变化显著影响疾病呈现和发病年龄.

科学领域:

神经遗传学神经遗传学
神经学神经学
分子生物学分子生物学

背景情况:

脊髓小脑缩症 (SCAs) 包含各种遗传形式,而不仅仅是三重重复扩张.
个别的非扩张性SCAs很少见,阻碍了基因型-表型相关性研究.

研究的目的:

调查非扩张性SCAs中的基因型-表型相关性.
分析不同基因和变异的临床特征,发病年龄和疾病进展.

主要方法:

选了756名具有7个非扩张SCA相关基因 (CACNA1A,PRKCG,AFG3L2,ITPR1,STUB1,SPTBN2,KCNC3) 变异的受试者.
根据基因和特定变异,比较发病时的年龄,疾病特征和进展.
分析了变体类型和蛋白质电荷变化对疾病表型的影响.

主要成果:

没有明显的特征可靠地区分这些SCAs.
几种基因 (CACNA1A,ITPR1,SPTBN2,KCNC3) 显示出成人和婴儿发病形式,呈现不同.
疾病进展一般缓慢,与STUB1相关的疾病进展最快.
在CACNA1A中的特定变异表现出广泛的发病年龄范围,甚至在家庭内.
在CACNA1A,ITPR1和SPTBN2中的变异类型和蛋白质电荷变化挑战了标准的致病性预测.

结论:

准确诊断非扩张性SCAs需要综合的临床和遗传专业知识.
表型变异性很大,受到特定遗传变异及其对蛋白质功能的影响.
仅靠下一代测序就不足以确定诊断,没有临床相关性.

关键词:

脊髓小脑缩症,SCA,CACNA1A,PRKCG,AFG3L2,ITPR1,STUB1,SPTBN2,KCNC3,发病的开始时间

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