Table 1 Heterozygous variants of uncertain clinical significance that were found in the DLB case cohort. The variant in DCTN1 was found in two DLB cases. All other variants were seen in single DLB cases. Variants are included in Table 1 if they were previously reported, but not fully established as pathogenic, and if they were present five times or less in the European (non-Finnish) population in gnomAD
From: Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies
Gene | Transcript | Variant | Number of DLB patients | GnomAD MAF (all populations) | GnomAD NFE AC (Total NFE AN) | Previously reported | Additional information | Ref |
|---|---|---|---|---|---|---|---|---|
APP | ENST00000346798 | c.2020G > A p.Glu674Lys | 1 | 0 | Not present | In AD: adjacent amino acid (p.A673T) protective, or (p.A673V) causes EOAD when homozygous | Variant newly identified here. Adjacent amino acid plays a role in disease | |
CHCHD2 | ENST00000395422 | c.10G > A p.Gly4Arg | 1 | 0.00002840 | 4 (128432) | 1 LBD patient | – | [54] |
DCTN1 | ENST00000361874 | c.2339 T > C p.Ile780Thr | 2 | 0.00003889 | 5 (129150) | 1 patient with FALS, control | Low frequency in gnomAD, but also found in a control | [35] |
GRN | ENST00000053867 | c.827C > T p.Ala276Val | 1 | 0.000007075 | 1 (129048) | 1 patient with an initial diagnosis of FTD which was changed to depression | Variant found in a patient included in a neurodegenerative disease cohort, but diagnosis was changed from FTD | [76] |
MAPT | ENST00000344290 | c.256G > A p.Gly86Ser | 1 | 0.00002901 | 4 (126300) | 1 patient with clinical FTD | Segregation not proven | [65] |
NOTCH3 | ENST00000263388 | c.1732C > T, p.Arg578Cys | 1 | 0.00003989 | 2 (113234) | Found in several CADASIL, but also seen in 1 control | Homozygous variant carrier had a mild phenotype | |
c.1733G > A p.Arg578His | 1 | 0.000007980 | 0 (113200) | p.Arg578Cys (different amino acid change) seen in CADASIL | Different amino acid change than previously reported, not cysteine changing | [14] | ||
c.1820G > A p.Arg607His | 1 | 0.000004000 | 1 (112826) | 1 CADASIL, and a different amino acid change, p.Arg607Cys seen in several CADASIL patients | Filtered site in gnomAD, may be false positive. Not cysteine changing | |||
SQSTM1 | ENST00000389805 | c.1210A > G p.Met404Val | 1 | 0.00001591 | 3 (113732) | Several families with Paget’s disease of bone | Variant shown to cause Paget’s disease of bone (not FTD-ALS) | |
TBK1 | ENST00000331710 | c.1150C > T p.Arg384Trp | 1 | 0.00002128 | 4 (128892) | p.Arg384Thr (different amino acid change) reported in 1 ALS | Different amino acid change than previously reported. Variation in the same amino acid in 2 different DLB cases in this study | [12] |
c.1151G > A p.Arg384Gln | 1 | 0.00008514 | 3 (128842) | p.Arg384Thr (different amino acid change) reported in 1 ALS | Different amino acid change than previously reported. Variation in the same amino acid in 2 different DLB cases in this study | [12] | ||
TIA1 | ENST00000433529 | c.1085C > T p.Pro362Leu | 1 | 0.00002121 | 2 (129146) | 2 s degree relatives with FTD/ALS | Unreplicated report suggests this variant causes ALS/FTD | [45] |