Gauquelin Laurence, Hartley Taila, Tarnopolsky Mark, Dyment David A, Brais Bernard, Geraghty Michael T, Tétreault Martine, Ahmed Sohnee, Rojas Samantha, Choquet Karine, Majewski Jacek, Bernier François, Innes Allan Micheil, Rouleau Guy, Suchowersky Oksana, Boycott Kym M, Yoon Grace
Division of Clinical and Metabolic Genetics, Department of Paediatrics The Hospital for Sick Children, University of Toronto Toronto Ontario Canada.
Division of Paediatric Neurology, Department of Paediatrics The Hospital for Sick Children, University of Toronto Toronto Ontario Canada.
Mov Disord Clin Pract. 2020 Sep 29;7(8):940-949. doi: 10.1002/mdc3.13086. eCollection 2020 Nov.
Cerebellar atrophy is a nonspecific imaging finding observed in a number of neurological disorders. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of conditions, rendering the approach to diagnosis challenging.
To define the spectrum of genetic ataxias associated with cerebellar atrophy in a Canadian cohort and the diagnostic yield of exome sequencing for this group of conditions.
A total of 92 participants from 66 families with cerebellar atrophy were recruited for this multicenter prospective cohort study. Exome sequencing was performed for all participants between 2011 and 2017 as part of 1 of 2 national research programs, Finding of Rare Genetic Disease Genes or Enhanced Care for Rare Genetic Diseases in Canada.
A genetic diagnosis was established in 53% of families (35/66). Pathogenic variants were found in 21 known genes, providing a diagnosis for 31/35 families (89%), and in 4 novel genes, accounting for 4/35 families (11%). Of the families, 31/66 (47%) remained without a genetic diagnosis. The most common diagnoses were channelopathies, which were established in 9/35 families (26%). Additional clinical findings provided useful clues to specific diagnoses.
We report on the high frequency of channelopathies as a cause of genetic ataxias associated with cerebellar atrophy and the utility of exome sequencing for this group of conditions.
小脑萎缩是在多种神经系统疾病中观察到的一种非特异性影像学表现。与小脑萎缩相关的遗传性共济失调是一组异质性疾病，这使得诊断方法具有挑战性。
确定加拿大队列中与小脑萎缩相关的遗传性共济失调的范围，以及外显子组测序对这组疾病的诊断率。
本多中心前瞻性队列研究招募了来自66个患有小脑萎缩家庭的92名参与者。作为加拿大两个国家研究项目之一“发现罕见遗传病基因”或“加强对罕见遗传病的护理”的一部分，在2011年至2017年期间对所有参与者进行了外显子组测序。
53%的家庭（35/66）得到了基因诊断。在21个已知基因中发现了致病变异，为31/35个家庭（89%）提供了诊断，在4个新基因中发现了致病变异，占4/35个家庭（11%）。66个家庭中，31个（47%）仍未得到基因诊断。最常见的诊断是通道病，在9/35个家庭（26%）中得到确诊。其他临床发现为特定诊断提供了有用线索。
我们报告了通道病作为与小脑萎缩相关的遗传性共济失调病因的高频率，以及外显子组测序对这组疾病的实用性。
