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. 2022 Feb 4;23(1):99.
doi: 10.1186/s12864-022-08343-9.

Mutation analysis of disease causing genes in patients with early onset or familial forms of Alzheimer's disease and frontotemporal dementia

María Pagnon de la Vega  1 , Carl Näslund  1 , RoseMarie Brundin  1 , Lars Lannfelt  1 , Malin Löwenmark  1 , Lena Kilander  1 , Martin Ingelsson  1   2   3 , Vilmantas Giedraitis  4
Affiliations

Mutation analysis of disease causing genes in patients with early onset or familial forms of Alzheimer's disease and frontotemporal dementia

María Pagnon de la Vega et al. BMC Genomics. .

Abstract

Background: Most dementia disorders have a clear genetic background and a number of disease genes have been identified. Mutations in the tau gene (MAPT) lead to frontotemporal dementia (FTD), whereas mutations in the genes for the amyloid-β precursor protein (APP) and the presenilins (PSEN1, PSEN2) cause early-onset, dominantly inherited forms of Alzheimer's disease (AD). Even if mutations causing Mendelian forms of these diseases are uncommon, elucidation of the pathogenic effects of such mutations have proven important for understanding the pathogenic processes. Here, we performed a screen to identify novel pathogenic mutations in known disease genes among patients undergoing dementia investigation.

Results: Using targeted exome sequencing we have screened all coding exons in eleven known dementia genes (PSEN1, PSEN2, APP, MAPT, APOE, GRN, TARDBP, CHMP2B, TREM2, VCP and FUS) in 102 patients with AD, FTD, other dementia diagnoses or mild cognitive impairment. We found three AD patients with two previously identified pathogenic mutations in PSEN1 (Pro264Leu and Met146Val). In this screen, we also identified the recently reported APP mutation in two siblings with AD. This mutation, named the Uppsala mutation, consists of a six amino acid intra-amyloid β deletion. In addition, we found several potentially pathogenic mutations in PSEN2, FUS, MAPT, GRN and APOE. Finally, APOE ε4 was prevalent in this patient group with an allele frequency of 54%.

Conclusions: Among the 102 screened patients, we found two disease causing mutations in PSEN1 and one in APP, as well as several potentially pathogenic mutations in other genes related to neurodegenerative disorders. Apart from giving important information to the clinical investigation, the identification of disease mutations can contribute to an increased understanding of disease mechanisms.

Keywords: APOE; APP; Alzheimer's disease; Exome sequencing; Frontotemporal dementia; MAPT; Neurodegenerative disorders; PSEN1; PSEN2.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Pedigrees of the families in which mutations were identified. The analyzed cases are indicated by numbers. Each pedigee is labeled by diagnosis and the nature of the mutation(s) identified. Filled symbols are affected family members. Slashed symbols are used for individuals known to be deceased. The numbers refer to the screened patients, corresponding to Table 1
See this image and copyright information in PMC

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