Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study.
Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study.
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DOI：
10.1007/s00415-022-11307-4
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发表时间：
2022-12
影响因子：
6
通讯作者：
Peall, Kathryn J.
中科院分区：
文献类型：
--
作者：
Wadon, Megan E.;Fenner, Eilidh;Kendall, Kimberley M.;Bailey, Grace A.;Sandor, Cynthia;Rees, Elliott;Peall, Kathryn J.
肌张力障碍的非运动症状谱尚不清楚。使用英国生物银行的数据，我们分析了迄今为止报道的最大肌张力障碍队列的临床表型和遗传信息。进行肌张力障碍和匹配对照队列的病例对照比较，以确定肌张力障碍中症状负担增加的领域（精神、疼痛、睡眠和认知）。全外显子组数据用于确定孟德尔遗传性肌张力障碍引起基因的变异率和可能的致病性，并与临床数据相关联。在肌张力障碍队列中，表型和遗传单核苷酸多态性（SNP）数据在混合模型分析中结合，以获得遗传信息的表型轴。共确定了1572例肌张力障碍患者，包括颈部肌张力障碍（n = 775）、眼睑痉挛（n = 131）、震颤（n = 488）和肌张力障碍，未指明（n = 154）组。表型模式突出了精神症状（焦虑和抑郁）、过度疼痛和睡眠障碍的优势。认知障碍仅限于前瞻性记忆和液体智力。全外显子组测序鉴定了肌张力障碍相关基因中的798个功能缺失变体、67个错义变体（MPC > 3）和305个其他形式的非同义变体（包括框内缺失、框内插入、停止缺失和开始缺失变体）。在肌张力障碍队列中确定了单一功能丧失变体（ANO 3）。结合SNP和临床数据确定了多个遗传信息表型轴，其中精神、疼痛和睡眠非运动域占优势。在所有形式的肌张力障碍中，精神、疼痛和睡眠症状都很明显。与遗传数据的结合突出了与临床实践中观察到的异质性一致的表型亚组。在线版本包含补充材料，可通过10.1007/s 00415 -022-11307-4获得。
The spectrum of non-motor symptoms in dystonia remains unclear. Using UK Biobank data, we analysed clinical phenotypic and genetic information in the largest dystonia cohort reported to date. Case–control comparison of dystonia and matched control cohort was undertaken to identify domains (psychiatric, pain, sleep and cognition) of increased symptom burden in dystonia. Whole exome data were used to determine the rate and likely pathogenicity of variants in Mendelian inherited dystonia causing genes and linked to clinical data. Within the dystonia cohort, phenotypic and genetic single-nucleotide polymorphism (SNP) data were combined in a mixed model analysis to derive genetically informed phenotypic axes. A total of 1572 individuals with dystonia were identified, including cervical dystonia (n = 775), blepharospasm (n = 131), tremor (n = 488) and dystonia, unspecified (n = 154) groups. Phenotypic patterns highlighted a predominance of psychiatric symptoms (anxiety and depression), excess pain and sleep disturbance. Cognitive impairment was limited to prospective memory and fluid intelligence. Whole exome sequencing identified 798 loss of function variants in dystonia-linked genes, 67 missense variants (MPC > 3) and 305 other forms of non-synonymous variants (including inframe deletion, inframe insertion, stop loss and start loss variants). A single loss of function variant (ANO3) was identified in the dystonia cohort. Combined SNP and clinical data identified multiple genetically informed phenotypic axes with predominance of psychiatric, pain and sleep non-motor domains. An excess of psychiatric, pain and sleep symptoms were evident across all forms of dystonia. Combination with genetic data highlights phenotypic subgroups consistent with the heterogeneity observed in clinical practice. The online version contains supplementary material available at 10.1007/s00415-022-11307-4.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
影响因子：
5
作者：
Fry A;Littlejohns TJ;Sudlow C;Doherty N;Adamska L;Sprosen T;Collins R;Allen NE
通讯作者：
Allen NE
影响因子：
30.8
作者：
Dahl A;Iotchkova V;Baud A;Johansson Å;Gyllensten U;Soranzo N;Mott R;Kranis A;Marchini J
通讯作者：
Marchini J
影响因子：
8.6
作者：
Albanese, Alberto;Bhatia, Kailash;Bressman, Susan B.;DeLong, Mahlon R.;Fahn, Stanley;Fung, Victor S. C.;Hallett, Mark;Jankovic, Joseph;Jinnah, Hyder A.;Klein, Christine;Lang, Anthony E.;Mink, Jonathan W.;Teller, Jan K.
通讯作者：
Teller, Jan K.