Phenotype-genotype discrepancies in the prospective Huntington at-risk observational study.
Phenotype-genotype discrepancies in the prospective Huntington at-risk observational study.
复制标题
前瞻性亨廷顿风险观察研究中的表型-基因型差异。
DOI：
10.1002/acn3.781
复制
发表时间：
2019
影响因子：
5.3
通讯作者：
PHAROSInvestigators
中科院分区：
文献类型：
--
作者：
Shoulson,Ira;Eberly,Shirley;Oakes,David;Kayson,Elise;Young,AnneB;PHAROSInvestigators
目的研究表型-基因型差异（PGDs），其中基因型隐藏和前瞻性判断亨廷顿病（HD）的运动发作发生在有非扩展（<37）胞嘧啶-腺嘌呤-鸟嘌呤（CAG）三核苷酸DNA重复序列的高危成人中。方法我们研究了前瞻性亨廷顿高危观察研究（PHAROS）中不知道个体CAG长度的研究者的前瞻性临床评估。他们招募并随访了未确诊的有HD风险的成年人，这些人选择不了解他们的基因状态。在1999年至2009年期间，对美国和加拿大43个亨廷顿研究组研究中心的受试者（n= 1001）进行了前瞻性和系统性评价。在每个研究中心，指定一名研究者进行综合临床评估，另一名研究者仅对运动检查进行评级。表型转换从一个“premanifest”状态到一个自信的“manifest”状态是基于调查人员的判断（诊断的置信水平）的锥体外系运动功能的HD.ResultsThere 20 PGDs，随着时间的推移有较低的严重运动评分比101与CAG ≥37表型转换，但更严重的运动评分比nonconversion。转换后，CAG ≥37扩展的受试者比< 37组中的PGD受试者在运动和认知方面恶化得更多。PGDs集中在三个网站和几个调查员，特别是评分员谁只评估了电机examination.InterpretationThe能力，及时和可靠的方式检测HD的临床发病仍然是关键的发展实验性治疗，旨在推迟HD的临床发病。综合临床评估是判定HD临床发作的更准确、可靠的依据，而不是单纯依靠判断HD的锥体外系特征。
ObjectiveTo examine phenotype–genotype discrepancies (PGDs) wherein genotype‐concealed and prospective judgments of the motor onset of Huntington disease (HD) occurred among at‐risk adults who had nonexpanded (<37) cytosine–adenine–guanine (CAG) trinucleotide DNA repeats.MethodsWe examined the prospective clinical assessments of investigators who were kept unaware of individual CAG lengths in the Prospective Huntington At‐Risk Observational Study (PHAROS) who enrolled and followed undiagnosed adults at risk for HD who chose not to learn their gene status. Subjects (n= 1001) at 43 Huntington Study Group research sites in the US and Canada were evaluated prospectively and systematically between 1999 and 2009. At each site, an investigator was designated to perform comprehensive clinic assessments and another investigator to rate only the motor examination. Phenoconversion from a “premanifest” status to a confidently “manifest” status was based on investigator judgment (diagnostic confidence level) of the extrapyramidal motor features of HD.ResultsThere were 20 PGDs that over time had less severe motor scores than the 101 phenoconversions with CAG ≥37, but more severe motor scores than nonconversions. Following conversion, subjects with CAG ≥37 expansions worsened more motorically and cognitively than PGD subjects in the < 37 group. PGDs were concentrated among three sites and a few investigators, especially raters who only assessed the motor examination.InterpretationThe ability to detect the clinical onset of HD in a timely and reliable fashion remains the key for developing experimental treatments aimed at postponing the clinical onset of HD. Comprehensive clinical evaluation is a more accurate and reliable basis for determining HD clinical onset than sole reliance on judging the extrapyramidal features of HD.