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Aging and disease    2018, Vol. 9 Issue (4) : 696-705     DOI: 10.14336/AD.2018.0208
Orginal Article |
The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia
Xu Yangqi1, Liu Xiaoli1,3, Shen Junyi1, Tian Wotu1, Fang Rong1,4, Li Binyin1, Ma Jianfang1, Cao Li1, Chen Shengdi1, Li Guanjun2,*, Tang Huidong1,*
1Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
2Shanghai Mental Health Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
3Department of Neurology, Shanghai Fengxian District Central Hospital, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital South Campus, Shanghai, China
4Department of Neurology, Ruijin Hospital North, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Abstract  

Our study aimed to identify the underlying causes in patients with early onset dementia by clinical and genetic exploration. We recruited a group of 38 patients with early-onset dementia. Firstly, hexanucleotide repeat expansions in C9ORF72 gene were screened in all subjects to exclude the possibility of copy number variation. Then, the whole exome sequencing (WES) was conducted, and the data were analyzed focusing on 89 dementia-related causing and susceptible genes. The effects of identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. There were no pathogenic expansions in C9ORF72 detected. According to the ACMG standards and guidelines, we identified five known pathogenic mutations, PSEN1 P284L, PSEN1c.857-1G>A, PSEN1 I143T, PSEN1 G209E and MAPT G389R, and one novel pathogenic mutation APP K687N. All these mutations caused dementia with the mean onset age of 38.3 (range from 27 to 51) and rapid progression. Eleven variants with uncertain significance were also detected and needed further verification. The clinical phenotypes of dementia are heterogeneous, with both onset ages and clinical features being influenced by mutation position as well as the causative gene. WES can serve as efficient diagnostic tools for different heterogeneous dementia.

Keywords frontotemporal dementia      Alzheimer’s disease      next-generation sequencing      variants classification     
Corresponding Authors: Li Guanjun,Tang Huidong   
About author:

These authors contributed equally to this work.

Issue Date: 01 August 2018
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Xu Yangqi
Liu Xiaoli
Shen Junyi
Tian Wotu
Fang Rong
Li Binyin
Ma Jianfang
Cao Li
Chen Shengdi
Li Guanjun
Tang Huidong
Cite this article:   
Xu Yangqi,Liu Xiaoli,Shen Junyi, et al. The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia[J]. Aging and disease, 2018, 9(4): 696-705.
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http://www.aginganddisease.org/EN/10.14336/AD.2018.0208     OR     http://www.aginganddisease.org/EN/Y2018/V9/I4/696
PhenotypeGenes
Early onset ADAPP, PSEN1, PSEN2
Late onset ADAPOE, A2M, ABCA7, ACE, APBB2, ATXN1, AKT1, AR, BIN1, BLMH, CASP3, CD2AP, CD33, CHCHD10, C9ORF72, CYP2C, CST3, CELF1, CLU, CR1, DNMT1, DSG2, EPHA1, ETS1, FERMT2, GSK3B, GRB2, HTR7, HFE, INPP5D, ITM2B, LRP1, MEF2C, MPO, MS4A4E, MPHOSPH1, MS4A6A, NME8, NOS3, NOTCH3, PICALM, PAXIP1, PLAU, PTK2B, SLC24A4, SORL1, TNF, TREM2, TYROBP, ZCWPW1
FTDBTNL2, C9ORF72, CFS1R, CHCHD10, CHMP2B, CST3, CTSC, DCTN1, FUS, GRN, hnRNPA1, hnRNPA2B1, MAPT, OPTN, PRKAR1B, PRNP, RAB38, SIGMAR1, SOD1, SQSTM1, TBK1, TARDBP, TMEM106B, TREM2, UBQLN2, VCP
DLBGBA, SNCA, SNCB
Other typesATP13A2, EPM2A, ITM2B, NHLRC1, PRICKLE1, TRPM7
Table 1  Genes associated with dementia.
Figure 1.  Magnetic resonance imaging (MRI), Alzheimer’s disease (AD) pathogenic mutations and Pedigrees for five cases

Brain MRI (T2W-FLAIR) images from AT001 (A), AT002 (D), AT040 (J), AT045 (M) and brain MRI (T2WI) images from AT003 (G). (B, E, H, K, N) are the Sanger sequencing results of AT001, AT002, AT003, AT040, and AT045. (C, F, I, L, O) indicate pedigrees of AT001, AT002, AT003, AT040, and AT045. * T2W-FLAIR: T2 weighted fluid-attenuated inversion recovery; T2WI: T2-weighted imaging.

CaseGeneZygosityMutation
(CDS)
Consequence at protein
level
Clinical diagnosisFrequency predictionSoftware predictionACMG

Esp65001000g2014East AsianPolyphen2SIFTMutation taster
AT008PSEN2Hetc.G640Tp.V214LAD/FTDNA0.00120.0025430.972/D0.09/Tdisease causingVUS
AT017PSEN2Hetc.G640Tp.V214LADNA0.00120.0025430.972/D0.09/Tdisease causingVUS
AT029GRNHetc.C1663Tp.R555WSDNANA0.00023250.98/D0.18/TpolymorphismVUS
AT013TREM2Hetc.C331Ap.Q111KADNANA0.00023130.998/D0.57/Tdisease causingVUS
AT015ABCA7Hetc.G5963Tp.C1988FADNA0.0009984NA1/D0/Ddisease causingVUS
AT022TRPM7Hetc.C2525Tp.T842MFTD-ALSNANANA0.945/P0.08/Tdisease causingVUS
AT020NME8Hetc.1008dupTp.R336fsFTD-ALSNANANANANAdisease causingVUS
AT032SORL1Hetc.C3238Tp.R1080CFTD0.000077NA5.998e-050.992/D0.06/Tdisease causingVUS
MPOHetc.G980Ap.R327HNANA6.057e-051/D0/Ddisease causingVUS
AT028APBB2Hetc.A433Tp.N145YFTD-parkinsonismNANANA0.561/P0.03/Ddisease causingVUS
AT037ATP13A2Hetc.C2806Tp.T1483AFTDNANANA1/D0.18/Tdisease causingVUS
AT041PSEN2Hetc.C505Ap.H169NADNA0.000199680.0023110.985/D0.05/Tdisease causingVUS
Table 2  Cases of variants with uncertain significance.
CaseDiagnosisGenetic resultAPOE genotype
AT001AD/FTDPSEN1: NM_000021: exon8: c.C851Tε3/ε3
AT002AD/FTDPSEN1: NM_007318: exon9: c.857-1G>Aε3/ε3
AT003AD/FTDPSEN1: NM_000021: exon5: c.T428Cε3/ε3
AT005AD/FTDNoneε4/ε3
AT006AD/FTDNoneε3/ε3
AT007AD/FTDNoneε3/ε3
AT008AD/FTDPSEN2: NM_000447: exon8: c.G640Tε4/ε3
AT010ADNoneε4/ε3
AT011ADNoneε4/ε3
AT012ADNoneε4/ε3
AT013ADTREM2: NM_001271821: exon2: c.C331Aε4/ε3
AT014ADNoneε2/ε3
AT015ADABCA7: NM_019112: exon45: c.G5963Tε4/ε3
AT017ADPSEN2: NM_000447: exon8: c.G640Tε4/ε4
AT019FTD-ALSNoneε3/ε3
AT020FTD-ALSNME8: NM_016616: exon13: c.1008dupTε3/ε3
AT021FTD-ALSNoneε3/ε3
AT022FTD-ALSTRPM7: NM_017672: exon19: c.C2525Tε4/ε3
AT025FTD-CBSNoneε3/ε3
AT026FTD-PSPSNoneε3/ε3
AT028FTD-parkinsonismAPBB2: NM_001166051: exon6: c.A433Tε3/ε3
AT029SDGRN: NM_002087: exon13: c.C1663Tε2/ε3
AT030bvFTDNoneε3/ε3
AT031bvFTDNoneε3/ε3
AT032bvFTDSORL1: NM_003105: exon23: c.C3238T
MPO: NM_000250: exon7: c.G980A
ε3/ε3
MPO: NM_000250: exon7: G980A
AT033bvFTDMAPT: NM_005910: exon13: G1165A
NM_005910
ε2/ε3
AT034bvFTDNoneε3/ε3
AT035bvFTDNoneε3/ε3
AT036bvFTDNoneε3/ε3
AT037bvFTDATP13A2: NM_001141974: exon25: c.C2806Tε3/ε3
AT038bvFTDNoneε3/ε3
AT039bvFTDNoneε3/ε3
AT040AD/FTDPSEN1: NM_000021: exon7: c.G626Aε4/ε3
AT041ADPSEN2: NM_000447: exon7: c.C505Aε3/ε3
AT042ADNoneε4/ε4
AT043bvFTDNoneε3/ε3
AT044ADNoneε2/ε3
AT045AD/FTDAPP: NM_000484: exon16: c.A2061Cε2/ε3
Table 3  APOE genotypes of all patients.
EthnicitySexAOPresenting symptomsFamily historyMMSEAPOEReference
KoreanF69Memory lossNA18ε3/4[39]
KoreanF54Memory loss, anomiaNo15ε3/3[37]
ChinaM63Memory lossNoNAε3/3[38]
ChinaF64Memory lossYesNAε4/4[38]
ChinaF50Memory loss and behavior changesNo12ε3/4This study
ChinaM48Memory lossNo15ε4/4This study
Table 4  Summary of basic characteristics of patients with V214L mutation in PSEN2.
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