Table 2.

Possibly causative variants identified by WES.

Patient	AAO	Family history	Gene	Nucleotide change	Amino acid change	Zygocity	Reference sequence	dbSNP ID	Allele frequency (gnomAD total)	Allele frequency (gnomAD Finnish)	CADD phred	PolyPhen2	Mutation Taster	SIFT	ACMG classification	Condition associated with the gene	Condition associated with the variant, reference	Detected in stroke-panel analysis	Detected in Exomiser analysis	Detected in rare variant analysis
102	57	n/a	CCM1 (KRIT1)	c.1565 T > C	p.(Ile522Thr)	Het	NM_194456.1	rs758188972	0.000007118	0.00001558	22,2	P	D	T	3	Cerebral cavernous malformations [24, 25]	Novel	Yes	No	No
102			ITM2B	c.193 C > T	p.(Leu65Phe)	Het	NM_021999.4		0	0	32	D	D	D	3	Cerebral amyloid angiopathy, retinal dystrophy [21–23]	Novel	Yes	Yes	Yes
137	65	No	CACNA1A	c.1348 T > C	p.(Ser450Pro)	Het	NM_001127222.1	rs1308599413	0.000007	0.00008	26,4	P	D	D	3	Episodic ataxia, familial hemiplegic migraine, spinocerebellar ataxia [27]	Novel	Yes	Yes	No
140	43	Yes	C1R	c.336 G > C	p.(Met112Ile)	Het	NM_001733.7	rs139531404	0.002823	0.002157	22,2	D	D	D	3	Ehlers–Danlos syndrome, periodontal type 1 [30]	Novel	Yes	No	No
140			CCM2	c.1346 T > G	p.(Ile449Ser)	Het	NM_001029835.2		0	0	22	D	D	D	3	Cerebral cavernous malformations [25, 26]	Novel	Yes	Yes	Yes
156	17	n/a	COL4A1	c.2440 G > A	p.(Gly814Arg)	Het	NM_001845.5		0	0	26,5	D	D	D	3	SVD [8]	Novel	Yes	Yes	Yes
156			PSEN2	c.53 C > T	p. (Thr18Met)	Het	NM_000447.2	rs143061887	0.00002	0	29	D	D	D	3	AD [17]	Novel	No	Yes	No
160	56	n/a	COL4A2	c.4291 C > T	p.(Arg1431Cys)	Het	NM_001846.3	rs139124960	0.000007	0	14,11	P	D	D	3	SVD [8]	Novel	Yes	Yes	No
184	71	n/a	NPPA	c.377 G > A	p.(Arg126Gln)	Het	NM_006172.4	rs1803268	0.00007592	0.0006427	19,69	D	N	D	3	Atrial fibrillation familial [32, 33]	Novel	Yes	No	No
185	62	Yes	COL4A1	c.401 C > T	p.(Pro134Leu)	Het	NM_001845.5	rs140517831	0.00042	0.002867	22,8	D	D	T	3	SVD [8]	Novel	Yes	No	No
204	69	n/a	APP	c.1795G > A	p.(Glu599Lys)	Het	NM_000484.3	rs140304729	0.00149	0.00836	20,5	D	D	D	3	AD [17]	PD, LBD [18–20]	Yes	No	No
235	56	n/a	NOTCH3	c.2149 C > T	p.(Arg717Cys)	Het	NM_000435.2	rs144163298	0.000036	0	29,3	D	D	T	3	CADASIL1 [5]	Novel	Yes	Yes	No
273	61	Yes	NOTCH3	c.323 G > A	p.(Cys108Tyr)	Het	NM_000435.2		0	0	33	D	D	D	4	CADASIL1 [14]	CADASIL [14]	Yes	Yes	Yes
290	56	n/a	TMEM106B	c.115 G > C	p.(Asp39His)	Het	NM_018374.3		0	0	25,3	D	D	D	3	FTLD, hypomyelinating leukodystrophy [28, 29]	Novel	No	Yes	Yes
379	70	Yes	HTRA1	c.961 G > A	p.(Ala321Thr)	Het	NM_002775.4	rs587776449	0.000081	0.00089	34	D	D	D	3	CARASIL [6], CADASIL2 [7, 16]	CARASIL [15]	Yes	No	No
379			COL4A1	c.401 C > T	p.(Pro134Leu)	Het	NM_001845.5	rs140517831	0.00042	0.002867	22,8	D	D	T	3	SVD [8]	Novel	Yes	No	No

ACMG variant classification [13] (5 = pathogenic, 4 = likely pathogenic, 3 = variant of unknown significance, 2 = likely benign, 1 = benign).

CADD Combined Annotation Dependent Depletion [40], algorithm for scoring the deleteriousness of variants (≥10 = belongs to 10% most deleterious variants in the human genome, ≥20 = belongs to 1% most deleterious variants in the human genome).

Polyphen2, MutationTaster, SIFT pathogenicity prediction tools (Polyphen2, D = damaging, P = possibly damaging, B = benign; MutationTaster, D = disease causing, N = polymorphism; SIFT, D = damaging, T = tolerated).

AAO age at onset, AD Alzheimer’s disease, FTLD frontotemporal lobar degeneration, het heterozygous, LBD Lewy Body Dementia, n/a no information available, PD Parkinson’s disease.