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. 2018 Jun;26(6):827-837.
doi: 10.1038/s41431-018-0117-3. Epub 2018 Feb 23.

Genetics of dementia in a Finnish cohort

Petra Pasanen  1   2 , Liisa Myllykangas  3 , Minna Pöyhönen  4   5 , Anna Kiviharju  6 , Maija Siitonen  7 , John Hardy  8 , Jose Bras  8   9   10 , Anders Paetau  3 , Pentti J Tienari  6   11 , Rita Guerreiro  8   9   10 , Auli Verkkoniemi-Ahola  11
Affiliations

Genetics of dementia in a Finnish cohort

Petra Pasanen et al. Eur J Hum Genet. 2018 Jun.

Abstract

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias. Variants in APP, PSEN1 and PSEN2 are typically linked to early-onset AD, and several genetic risk loci are associated with late-onset AD. Inherited FTD can be caused by hexanucleotide expansions in C9orf72, or variants in GRN, MAPT or CHMP2B. Several other genes have also been linked to FTD or FTD with motor neuron disease. Here we describe a cohort of 60 Finnish families with possible inherited dementia. Our aim was to clarify the genetic background of dementia in this cohort by analysing both known dementia-associated genes (APOE, APP, C9ORF72, GRN, PSEN1 and PSEN2) and searching for rare or novel segregating variants with exome sequencing. C9orf72 repeat expansions were detected in 12 (20%) of the 60 families, including, in addition to FTD, a family with neuropathologically verified AD. Twelve families (10 with AD and 2 with FTD) with representative samples from affected and unaffected subjects and without C9orf72 expansions were selected for whole-exome sequencing. Exome sequencing did not reveal any variants that could be regarded unequivocally causative, but revealed potentially damaging variants in UNC13C and MARCH4.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Schematic presentation of the study describing the workflow of genetic examinations. WES whole-exome sequencing
Fig. 2
Fig. 2
Proportions of C9orf72 expansions in clinical frontotemporal dementia (FTD), Alzheimer’s disease (AD) and unspecified dementia in a cohort of 60 families. DLB dementia with Lewy bodies
Fig. 3
Fig. 3
Pedigrees of the families with rare variants verified by Sanger sequencing. DNA samples were available from individuals marked with an asterisk. APOE genotypes are also marked in the pedigree. a Family Fam-56 with the CLU p.(Thr203Ile) variant. Heterozygous variant (−/+), homozygous wild-type allele (−/−). b Family Fam-15 with the PCDH11X p.(Asp760Val) variant. Heterozygous variant (−/+), homozygous wild-type allele (−/−), hemizygous variant (+), hemizygous wild-type allele (−). c Family Fam-49 with the UNC13C p.(Lys443del) variant. Heterozygous variant (−/+), homozygous wild-type allele (−/−). d. Family Fam-13 with the MARCH4 p.(Lys211Glu) variant. Heterozygous variant (−/+), homozygous wild-type allele (−/−). e Family Fam-59 with the MARCH4 p.(Trp13Cys) variant. Heterozygous variant (−/+), homozygous wild-type allele (−/−)
See this image and copyright information in PMC

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