Identification of a novel mutation in APP gene in a Thai subject with early-onset Alzheimer’s disease

Figures & data

Figure 1 Family tree of patient (II-2) with APP V604M in his early onset 50s.

Abbreviation: APP, amyloid precursor protein.

Figure 2 Structural MRI sequences. (A) T1-weighted MRI image of the patient with Alzheimer’s disease with sagittal view. (B) Coronal T2WI. (C) Axial T2WI.

Note: The arrows point to the hippocampal atrophy.
Abbreviation: MRI, magnetic resonance imaging.

Figure 3 NGS data identifying the APP p.V604M mutation in the proband.

Notes: NGS data quality was relatively high. The identified mutation was confirmed via standard sequencing.
Abbreviations: APP, amyloid precursor protein; NGS, next generation sequencing.

Figure 4 Bulkiness profile of wild-type and p.V604M mutant APP proteins.

Notes: Dotted line represents the shift in the bulkiness around the mutant site. X axis represents amino acid sequence from N-to C-terminal. Y axis represents scores computed by each algorithm. The prediction was done by ProtScale program at ExPASy server.
Abbreviation: APP, amyloid precursor protein.

Figure 5 In silico 3D modeling for APP p.V604M.

Note: Differences between the normal and mutant protein were highlighted where valine was labeled with yellow, whereas methionine was labeled with purple.
Abbreviation: APP, amyloid precursor protein.

Table S1 Mutations, discovered in the panel of 50 genes by NGS

Chr	Gene	Mutation	RS_ID	Frequency			In silico prediction			Remarks
				KCDC	ExAC	1000 genomes	PolyPhen2 HumDiv	Sift score	Provean
1	PINK1	A340T	rs3738136	0.305466	0.09211	0.092	0.605 (D)	0.05 (D)	−3.91 (D)	May be risk factor for progressive supranuclear palsy
		N521T	rs1043424	0.377010	0.09211	0.2811	0.005 (B)	0.24 (T)	−0.94 (N)	Unclear significance
	CR1	T2060S	rs4844609	1	0.9853	0.9922	0.95 (D)	0.019 (D)	0.55 (N)	Common variant, possible AD risk factor
2	ALS2	V368M	rs3219156	1.0	0.9106	0.8983	0.009 (B)	0.191 (T)	−0.06 (N)	Common variant, may not be significant
5	CSF1R	L536V	rs55942044	NA	NA	NA	0.99 (D)	0.003 (D)	−2.11 (D)	Probable novel variant, predicted to be damaging
6	FIG4	V654A	rs9885672	0.354502	0.2753	0.2953	0 (B)	0.3 (T)	0.95 (N)	May be a benign allele
	PARK2	V380L	rs1801582	0.044212	0.1646	0.144	0 (B)	0.37 (T)	−0.09 (N)	Probable benign variant
10	CTNNA3	S596N	rs4548513	0.431672	0.4120	0.472	0.001 (B)	1 (T)	2.04 (N)	Possible risk factor for LOAD and autism
11	BACE1	C481R	rs539765	1.0	1.0	1.0	0 (B)	0.4 (T)	1.45 (N)	Common variant, unknown significance
	SORL1	A528T	rs2298813	0.04219	0.07219	0.08219	0.96 (D)	0.31 (T)	−2.2 (D)	Probable AD risk factor
		E1074Q	rs1699107	0.9885	0.9949	1.000000	0 (B)	0.16 (T)	−0.15 (N)	Common variant, unknown significance
		I1967V	rs1792120	0.9953	1.000000	0.9853	0.003 (B)	1 (T)	0.27 (N)	Unknown significance
12	LRP6	V1062I	rs2302685	0.922830	0.8474	0.8861	0 (B)	1 (T)	0.96 (N)	Common mutation, possible AD risk factor
	LRRK2	R50H	rs2256408	1.0	0.9911	0.9739	0 (B)	1 (T)	0.94 (N)	Common variant, unknown significance
		M2397T	rs3761863	0.3613	0.4613	0.6846	0 (B)	0.466 (T)	−1.16 (N)	Unknown significance, PD risk factor and and Crohn’s disease
15	SPG11	F463S	rs3759871	0.479100	0.4657	0.492	0.009 (B)	0.341 (B)	−1.27 (N)	Probable benign
19	ABCA7	E188G	rs3764645	0.428457	0.4838	0.412	0.06 (B)	0.67 (T)	−0.87 (N)	Unclear significance
		R1349Q	rs3745842	0.366559	0.4433	0.43799	0.004 (B)	0.54 (T)	0.05 (N)	Common variant, unknown
		G1527A	rs3752246	0.661576	0.8375	0.8237	0 (B)	0.877 (T)	2.70 (N)	Possible AD risk factor
		A2045S	rs4147934	0.422830	0.7317	0.631	0.051 (B)	0.96 (T)	0.06 (N)	Unknown significance
	NOTCH3	A2223V	rs1044009	0.59003	0.6937	0.6309	0.003 (B)	0.175 (T)	−1.46 (N)	Common variant, unknown significance
20	PRNP	E219K	rs1800014	0.057074	0.008728	0.009728	0.003 (B)	0.035 (D)	0.00 (N)	Pathogenic nature complicated
21	APP	V604M	NA	NA	NA	NA	0.474 (D)	0.095 (T)	−0.72 (N)	Probable novel variant may be involved in disease phenotypes

Abbreviations: NGS, next-generation sequencing; AD, Alzheimer’s disease; APP, amyloid precursor protein; PD, Parkinson disease; B, Benign; T, Tolerant; N, Neutral; Chr, chromosome; D, damaging; NA, not available; KCDC, Korea Centers for Disease Control & Prevention; ExAC, The Exome Aggregation Consortium; LOAD, late-onset Alzheimer’s disease; PolyPhen2, Polymorphism Phenotyping version 2; RS_ID, single nucleotide polymorphism identifier.