Frequency of frontotemporal dementia gene variants in C9ORF72, MAPT, and GRN in academic versus commercial laboratory cohorts

Figures & data

Table 1 Demographic characterization of patients with pathogenic/likely pathogenic variants in FTLD-associated genes at UCSF and commercial clinical laboratory

Patient demographics	GRN		MAPT		C9orf72
	UCSF	Clinical laboratory	UCSF	Clinical laboratory	UCSF	Clinical laboratory
Age^a (years)	62.95±7.0	60.9±6.9	55.1 ± 10.8	59.1 ± 10.7	60.9±7.2	59.3± 10.0
sex, n (%)
Male	8 (40)	9 (37.5)	4 (44.4)	9 (47.4)	33 (67.3)	170 (50.2)
Female	12 (60)	15 (62.5)	5 (55.6)	10 (52.6)	16 (32.7)	169 (49.8)
Total no.	20	24	9	19	49	344^b

Notes: ^aAge for the USCF cohort was defined as age at the first visit. Age for Quest cohort is age when testing was performed. ^bSex was unavailable for five patients in the commercial clinical laboratory cohort. In the GRN mutations in the UCSF cohort, 85% (n=17) of patients had autosomal dominant family history of dementia (at least one first-degree relative), 10% (n=2) had family history unknown, and 5% (n=1) were negative for a family history of dementia. In patients with pathogenic mutations in MAPT in the UCSF cohort, 88% (n=8) had an autosomal dominant family history of dementia (at least one first-degree relative) and 12% (n=1) had a negative family history. In patients with pathogenic C9orf72 expansions in the UCSF cohort, 51% (n=25) had an autosomal dominant family history of dementia (at least one first-degree relative), 33% (n=16) had a negative family history, and 14% (n=7) had an unknown family history. Family history data were not available for the commercial laboratory cohort.

Abbreviations: FTLD, frontotemporal lobar degeneration; UCSF, University of California, San Francisco.

Figure 1 GRN variants in cohorts from UCSF and a Commercial Clinical Laboratory.

Notes: UCSF variants appear in blue text above the gene, while commercial clinical laboratory variants appear in green below the gene. Variants that appeared in both cohorts are indicated in underlined, bold typeface. GRN is located on chromosome 17q21 and consists of 13 exons encoding a highly glycosylated 593-amino acid precursor protein with a predicted molecular mass of 63.5 kDa.^{12 a}All variants were classified as pathogenic or likely pathogenic, except for c.415T>C, which is a missense variant classified as a risk allele.
Abbreviation: UCSF, University of California, San Francisco.

Figure 2 Neuroimaging from select GRN variant cases.

Notes: Structural brain MRI at patients’ first presentation to UCSF. GRN variant and CDR total score (with larger scores demonstrating worse clinical disease severity) at the time of scan are provided below each of three patients’ representative structural brain images in coronal (A and B) or axial (C) orientation. Images are in radiological orientation with the right side of the brain presented as the left side of the image. All patients showed asymmetric atrophy, predominantly in the frontal and temporal lobes, which is typical of GRN mutation carriers.¹⁸
Abbreviations: CDR, clinical dementia rating; R, right; L, left.

Table S1 Transcript IDs

	GRN	MAPT
UCSF	NM 002087.2	NM 005910.4
Clinical laboratory	NM_002087.2	NM_0059I0.4

Notes: Variants are mapped to human genome build GRCh37 (hg19). The “A” of the ATG start codon is numbered as nucleotide position one (c.1). The first exon in both GRN and MAPT is noncoding. It is described as exon 1 here, but other literature may describe it as Exon 0. cDNA numbering may also differ subtly from other literature, which may describe the first nucleotide of the first, non-coding exon as c.1.

Abbreviations: UCSF, University of California, San Francisco; IVS, intervening sequence.

Table S2 GRN variants included in this study; count in the commercial clinical laboratory/UCSF cohort and overall ExAC frequencies^a

cDNA (NM_002087.2)	Protein (NP_002078.1)	Clinical laboratory count (n=24)	UCSF count (n=20)	Instances in ExAC, (total frequency)	Major ethnic group in ExAC^c
c.1A>T	p.Met1Leu	0	1	1, (8.21 × 10−^5)	SAS
c.2T>C	p.Met1Thr	1	0	1, (8.24×10−^6)	NFE
c.26C>A	p.Ala9Asp	2	0	0
c.154delA	p.Thr52Hisfs*2	0	1	0
c.295_308delTGCCCACGGGGCTT	p.Cys99Profs*15	0	1	0
c.264+1 G>A	Splice site	1	0	0
c.264+2 T>C	Splice site	1	0	0
c.328C>T	p.Arg110*	2	2	1, (8.51 × 10−^6)	NFE
c.347 C>A	p.Ser116*	0	1	0
c.349+1 G>A	Splice site	1	0	0
c.388_39ldelCAGT	p.Gln130Serfs*125	2	0	1, (8.24×10−^6)	NFE
c.415 T>C^b	p.Cys139Arg	0	1	22, (1.81 × 10−^4)	I4X NFE, 7X SAS,IX AMR
c.472_496dup	p.Pro166Leufs*2	0	1	0
c.592_593 delAG	p.Arg198Glyfs*19	2	1	0
c.708+1G>A	Splice site	1	0	1, (8.28×10−^6)	FIN
c.745C>T	p.Gln249*	1	0	0
c.709-2A>G	Splice site	3	0	0
c.836-1 G>C	Splice site	0	1	0
c.898C>T	p.Gln300*	1	2	0
c.910_911 dupTG	p.Trp304Cysfs*58	1	0	1, (8.26×10−^6)	NFE
c.1145 del C	p.Thr382Serfs*30	0	1	0
c.1157G>A	p.Trp386*	1	0	0
c.1216C>T	p.Gln406*	0	1	0
c.1263_1264insGAAGCGAG	p.Ile422Glufs*72	0	1	0
c.1336C>T	p.Gln446*	1	0	0
c.1477C>T	p.Arg493*	1	5	0
c.1562G>A	p.Cys521Tyr	1	0	5, (4.12 × 10−^5)	3X in AMR, 2X in NFE
c.1414-15_1591 del	Splice site	1	0	0

Notes: ^aA total of 28 different GRN variants were found in the 44 unrelated subjects included in the final analysis. ^bc.415C>T was classified as a risk allele. ^cThe ExAC contains exome sequence data for >60,000 individuals of various ethnic backgrounds. SAS indicates South Asian, NFE indicates Non-Finnish European, AMR indicates Latino, and FIN indicates Finnish.

Abbreviations: UCSF, University of California, San Francisco; ExAC, Exome Aggregation Consortium.

Table S3 Pathogenic/likely pathogenic MAPT variants included in this study; count in commercial clinical laboratory/UCSF cohort and overall ExAC frequencies^a

cDNA (NM_0059I0.4)	Protein	Clinical laboratory count	UCSF count	Instances in ExAC, (total frequency)	Major ethnic group in ExAC^b
c.742 G>A	P.Val248Met	0	1	3, (2.52×10−^5)	2X NFE, 1X EAS
c.837 T>A	P.Asn279Lys	1	0	0
c.902 C>T	P.Pro301 Leu	11	3	0
c.1066T>A	P.Ser356Thr	0	1	0
c.915+14C>T	Splice site	1	0	0
c.915+16C>T	Splice site	3	2	2, (8.08×10−^5)	1X AFR, 1X NFE
c.915+19C>G	Splice site	1	0	1, (8.08×10−^5)	1X AFR, 1X NFE
c.1165 G>A	P.Gly389Arg	2	0	0
c.1216C>T	P.Arg406Trp	0	2	1, (8.27×10−^6)	NFE

Notes: ^aA total of nine different MAPT variants were found in 28 unrelated subjects included in the final analysis. ^bThe ExAC contains exome sequence data for >60,000 individuals of various ethnic backgrounds. NFE indicates Non-Finnish European, EAS indicates East Asian, AFR indicates African/African American.

Abbreviations: UCSF, University of California, San Francisco; ExAC, Exome Aggregation Consortium.

Table S4 Type and quantity of overlap in MAPT and GRN variants between cohorts from UCSF and a commercial clinical laboratory

Gene	Protein	UCSF, n (%)	Clinical laboratory, n (%)	Total occurrences
GRN (NM_002087.2)
	P.Arg110*	2 (10)	2 (8)	4
	P.Arg198Glyfs*19	1 (5)	2 (8)	3
	P.Gln300*	2 (10)	1 (4)	3
	P.Arg493*	5 (25)	1 (4)	6
MAPT (NM_005910.4)
	c.915+16 C>T^a	2 (22)	3 (15)	5
	P.Pro301 Leu	3 (33)	11 (58)	14

Note: ^aMAPT c.915+16 C>T is located in the IVS region and has no protein product.

Abbreviations: UCSF, University of California, San Francisco; IVS, intervening sequence; Arg, arginine; Pro, proline; Leu, leucine; Glyfs, glycine frame shift; Gln, glutamine.

Figure S1 Selection of participants from UCSF.

Notes: The UCSF dataset included a total of 153 pathogenic/likely pathogenic FTLD variants, 89 of which were C9orf72 pathogenic expansions, 46 GRN, and 18 MAPT. We obtained the subset of unrelated patients (blue icon) by removing variants found in family members of probands.
Abbreviations: UCSF, University of California, San Francisco; FTLD, frontotemporal lobar degeneration.

Figure S2 Selection of participants from a commercial clinical laboratory.

Notes: The commercial clinical laboratory dataset included a total of 397 pathogenic/likely pathogenic FTLD variants, 345 of which were C9orf72 pathogenic expansions, 29 GRN, and 23 MAPT. We obtained the subset of unrelated patients (green icon) by removing variants ordered through family test codes (gray). There was no family test code for C9orf72; thus, all pathogenic expansions were included in the final analysis.
Abbreviation: FTLD, frontotemporal lobar degeneration.

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