一个携带新型 PSEN1 突变（Ile416Thr）的大家族的遗传起源。
Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr).
机构信息
Grupo de Neurociencias de Antioquia, School of Medicine, Universidad de Antioquia, Medellín, Antioquia, Colombia.
Grupo de Neurociencias de Antioquia, School of Medicine, Universidad de Antioquia, Medellín, Antioquia, Colombia; Neuroscience Research Institute, University of California, Santa Barbara, CA, USA; Department of Molecular Cellular and Developmental Biology University of California, Santa Barbara, CA, USA.
出版信息
Alzheimers Dement. 2019 May;15(5):709-719. doi: 10.1016/j.jalz.2018.12.010. Epub 2019 Feb 10.
INTRODUCTION
A small percentage of Alzheimer's disease (AD) cases are caused by genetic mutations with autosomal dominant inheritance. We report a family with a novel variant in PSEN1.
METHODS
We performed clinical and genetic evaluation of 93 related individuals from a Colombian admixed population. 31 individuals had whole-genome sequencing.
RESULTS
Genetic analysis revealed a missense variant in PSEN1 (NM_000021.3: c.1247T>C p.Ile416Thr), which originated on an African haplotype and segregated with AD logarithm of the odds score of 6. Their clinical phenotype is similar to sporadic AD except for earlier age at onset: the mean age at onset for mild cognitive impairment was 47.6 years (standard deviation 5.83) and for dementia 51.6 years (standard deviation 5.03).
DISCUSSION
Ile416Thr is a novel pathogenic variant that causes AD in the sixth decade of life. The history of the region that included slave importation and admixtures within a confined geographic locale represents a "mini-population bottleneck" and subsequent emergence of a rare dominant mutation.
简介
一小部分阿尔茨海默病（AD）病例是由具有常染色体显性遗传的基因突变引起的。我们报告了一个具有 PSEN1 新变异的家族。
方法
我们对来自哥伦比亚混合人群的 93 名相关个体进行了临床和遗传评估。31 名个体进行了全基因组测序。
结果
遗传分析显示 PSEN1 中的错义变异（NM_000021.3: c.1247T>C p.Ile416Thr），该变异起源于非洲单倍型，与 AD 的对数优势评分 6 相关。他们的临床表型与散发性 AD 相似，只是发病年龄更早：轻度认知障碍的平均发病年龄为 47.6 岁（标准差为 5.83），痴呆的平均发病年龄为 51.6 岁（标准差为 5.03）。
讨论
Ile416Thr 是一种新的致病性变异，可导致 60 岁左右发生 AD。该地区曾有奴隶进口和在有限地理区域内混合的历史，代表了一个“小种群瓶颈”，随后出现了罕见的显性突变。
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