National Institute of Neurological Disorders and Stroke (NINDS), Family Study of Essential Tremor (FASET), Identification of Susceptibility Genes for Essential Tremor

The Familial Study of Essential Tremor (FASET) was designed to identify susceptibility genes for Essential Tremor. ET is among the most common neurological diseases with a prevalence (age > 40 years) estimated to be 4.0% and prevalence in advanced age (> 90 years) exceeding 20%. ET, often referred to as "familial tremor", is generally regarded as a highly genetic disorder with families, with affected members over multiple generations, and twin studies show high concordance among monozygotic twins. Probands (affected with ET) and relatives were enrolled in a family study of ET at Columbia University, New York between 2011 - 2014. The study was approved by the Institutional Review Board at Columbia University and written informed consent was obtained from all enrollees. The criteria for enrollment were: 1) the proband had early-onset ET with age at onset < 50 years, 2) the proband had a diagnosis of definite or probable ET, 3) in addition to the proband, there were at least two affected relatives in the family, 4) additional affected and unaffected family members were willing to participate in the study, and 5) the families contained more than two affected individuals in different generations. Blood samples were also collected for genetic research. For the genetic analyses, we excluded enrollees that we or others had diagnosed with Parkinson's disease (PD) or dystonia. The final sample includes 52 families (52 probands [affected with ET]) and 155 relatives). The number of affected individuals enrolled per family ranged from 3 - 7 (mean = 4.1). Genetic samples from FASET were analyzed with whole genome SNP genotyping (for linkage analyses) and whole exome sequencing. It is hoped that this resource will better help researchers to understand the genetic causes of ET and underlying disease pathogenesis.]]>
Home Visit Questionnaire (A - Form)Archimedes Spiral SheetsRegistration Form (R - Form)Spiral InstructionsVideo Evaluation Form (Form VE)Spirals Example Home VisitVerbal Consent FormAn in-person evaluation was performed on all participants, during which they completed demographic, medical history, and family history questionnaires, and underwent a videotaped neurological examination, from which a total tremor score (range= 0 - 36) was assigned. After review of the questionnaires and videotaped examinations, the diagnosis of ET was then reconfirmed by a senior neurologist specializing in movement disorders (E.D.L.) using reliable and valid research criteria. All ET diagnoses (possible, probable, definite) required, at a minimum, moderate or greater amplitude kinetic tremor on at least three tasks, and an absence of other etiologies (e.g., dystonia, Parkinson's disease, drug-induced tremor). Probable ET required such tremor on at least four tasks and definite ET required this as well as postural tremor of at least moderate amplitude. As such, all ET diagnoses met and exceeded the requirements outlined in the Consensus Statement on Tremor of the Movement Disorders Society.]]>
September 2011 - Study visits and enrollment begins March 2014 - Study visits and enrollment of families completed June 2014 - Whole genome SNP genotyping completed August 2014 - End of study (Study in no cost extension) December 2014 - Exome sequencing completed July 2015 - Study closed end of no cost extensionJuly 2015 -New funding periodJuly 2015-Study visits and enrollment beginsApril 2018-Study visits and enrollment of families completedApril 2019-Whole genome sequencing completedFebruary 2020-Linkage and Rare Variant analyses completedJuly 2020-End of study (Study in 1st No cost extension)August 2021-Study in 2nd No cost extensionSeptember 2021-Completion of dbGaP submission of phenotype and genotype data  ]]>

特发性震颤家族研究（Familial Study of Essential Tremor, FASET）旨在鉴定特发性震颤（Essential Tremor, ET）的易感基因。ET是最常见的神经系统疾病之一，40岁以上人群患病率约为4.0%，90岁以上高龄人群患病率则超过20%。ET常被称为“家族性震颤”，一般被认为是高度遗传性疾病，多个世代均存在受累成员，且双生子研究显示同卵双生子间震颤的共患率极高。

2011年至2014年间，研究团队于美国纽约哥伦比亚大学开展ET家族研究，招募了ET先证者（已确诊ET）及其亲属。本研究经哥伦比亚大学机构审查委员会（Institutional Review Board）批准，所有入组者均签署书面知情同意书。

入组标准如下：1）先证者为早发性ET，发病年龄小于50岁；2）先证者确诊为很可能或确诊ET；3）除先证者外，家系中至少还有2名受累亲属；4）其余受累及未受累的家庭成员均自愿参与本研究；5）家系内不同世代均存在至少2名受累个体。

研究同时采集血液样本用于遗传学研究。遗传学分析阶段排除了经本团队或其他机构诊断为帕金森病（Parkinson's Disease, PD）或肌张力障碍的入组者。最终样本共纳入52个家系（含52名ET先证者）及155名亲属，每个家系的受累入组成员数为3~7例（平均4.1例）。FASET的遗传样本采用全基因组SNP基因分型（用于连锁分析）及全外显子组测序进行检测。本数据集旨在助力研究者深入阐明ET的遗传病因及潜在发病机制。

相关评估工具包括：家庭访视问卷（A表）、阿基米德螺旋描记板、登记表（R表）、螺旋描记指导手册、视频评估表（VE表）、螺旋描记示例家庭访视、口头知情同意书。所有参与者均接受当面评估：填写人口统计学、病史及家族史问卷，并接受录像神经科检查，据此计算震颤总评分（评分范围0~36分）。

在审阅问卷及录像检查结果后，由一名专攻运动障碍性疾病的资深神经科医师（E.D.L.）采用经过验证的可靠研究标准，对ET诊断进行复核。所有ET诊断（可能、很可能、确诊）均需满足以下最低要求：至少三项任务中出现中等及以上幅度的动作性震颤，且无其他震颤病因（如肌张力障碍、帕金森病、药物诱发性震颤）。很可能ET需在至少四项任务中出现上述震颤，确诊ET则需同时存在至少中等幅度的姿势性震颤。综上，所有ET诊断均达到并超出了运动障碍学会震颤共识声明中的相关标准。

研究时间线如下：
2011年9月：研究访视及入组启动
2014年3月：家系研究访视及入组完成
2014年6月：全基因组SNP基因分型完成
2014年8月：研究进入无经费延长期，研究暂告一段落
2014年12月：全外显子组测序完成
2015年7月：无经费延长期结束，研究关闭
2015年7月：获得新资助周期
2015年7月：研究访视及入组重新启动
2018年4月：家系研究访视及入组完成
2019年4月：全基因组测序完成
2020年2月：连锁分析及罕见变异分析完成
2020年7月：研究进入首次无经费延长期，研究暂告一段落
2021年8月：研究进入第二次无经费延长期
2021年9月：表型及基因型数据提交至dbGaP数据库完成