Phenotype Heterogeneity and Genotype Correlation of MAPT Mutations in a Chinese PUMCH Cohort
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Phenotype Heterogeneity and Genotype Correlation of MAPT Mutations in a Chinese PUMCH Cohort Chenhui Mao 1 & Liling Dong 1 & Jie Li 1 & Xinying Huang 1 & Dan Lei 1 & Jie Wang 1 & Shanshan Chu 1 & Caiyan Liu 1 & Bin Peng 1 & Liying Cui 1 & Jing Gao 1 Received: 24 July 2020 / Accepted: 25 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Frontotemporal dementia (FTD) is a heterogeneous disease both clinically and pathologically. Genetic mutation in microtubuleassociated protein tau (MAPT) is the most common cause of FTD, and the phenotype is related to the mutation location. However, the phenotype and genotype correlation varies somewhat among different cohorts and ethnicities. Whole-genome next-generation sequencing (NGS) was carried out for 1351 patients with dementia at Peking Union Medical College Hospital. MAPT variations classified as pathogenic and of uncertain significance were identified. Demographic information, clinical presentations, and neuroimaging were collected, and the phenotype-genotype correlation was analyzed with a concurrent literature review. Twenty-four patients were enrolled; 8 patients carrying the D177V mutation are discussed separately. The average onset age was young, and most of them had a positive family history. Cognitive dysfunction, behavior, and personality changes as well as aphasia were the most common presentations. Most structural MRIs showed asymmetrical atrophy of the temporal lobe, with/without similar changes in the frontal lobe. L266V carriers presented with youngest onset typical behavior variant FTD or aphasia; P301L carriers presented with behavior variant FTD or aphasia. Functional MRI and molecular imaging also showed that the involved areas were similar to those with structural atrophy. D296N carriers presented atypical parkinsonism and cognitive dysfunction at older ages. Eight D177V carriers had extraordinarily different manifestations. The clinical phenotype of most of them was not FTD, though cerebral vascular lesions were obvious in some of them. MAPT mutation is rare in Chinese dementia patients. The phenotype and genotype correlation is specific and overlaps. The D177V mutation is possibly not directly pathogenic in our cohort. Some of the variants might increase the genetic risk of neurodegenerative diseases. Keywords Frontotemporal lobar degeneration . Microtubule-associated protein tau . Phenotype . Variations . Next generation sequencing
Introduction Frontotemporal dementia (FTD) is the third most common form of dementia and is a clinical term encompassing a group of neurodegenerative diseases (Bang et al. 2015). Frontotemporal dementia is classified into three clinical variants: behavioral-variant frontotemporal dementia (bv-FTD), nonfluent variant primary progressive aphasia (nf-PPA), and semantic-variant primary progressive aphasia (sv-PPA).
* Jing Gao [email protected] 1
Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Dongcheng Di
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