Table 1.
Results of linkage studies in patients with familial essential tremor (ET).
| Country | Locus | Chromosome | MIM/ Gene ID |
Study Subjects | Main Findings/Comments | [Ref] |
|---|---|---|---|---|---|---|
| Iceland | ETM1 (FET1) | 3q13 | 190300/2111 | Genome-wide scan study involving 16 Icelandic families (75 affected individuals) with ET in an autosomal dominant pattern | Gene mapped at chromosome 3q13 with a genome-wide significance assuming an autosomal-dominant model (parametrically LOD score = 3.71 and non-parametrically LOD score = 4.70). The highest single-family LOD score was 1.29 |
[29] |
| United States of America | ETM1 (FET1) | 3q13 | 190300/2111 | Linkage analysis with microsatellite markers for ETM1, ETM2, and chromosome 4p in 38 members of a six-generation family with ET | Lack of association with the analyzed loci, including ETM1 and with chromosome 4p | [33] |
| Russia | ETM1 (FET1) | 3q13 | 190300/2111 | Linkage analysis for ETM1 and ETM2 loci, and for locus DYT1 on chromosome 9q32-34 in a group of Slavonic (11 patients) and Tajik (19 patients) families with ET. | Linkage to locus ETM1 in 4 families (maximum pairwise LOD score 2.46, maximum combined multipoint LOD score was 3.35 for marker D3S3720) and a common “mutant” haplotype for markers D3S3620, D3S3576, and D3S3720 in a 2 Cm chromosomal region | [34] |
| Italy | ETM1 (FET1) | 3q13 | 190300/2111 | Linkage analysis of 3 loci previously associated with ET (ETM1, ETM2, and a locus on 6p23 (ETM3)) in fifth-generation Italian kindred with autosomal-dominant ET (22 clinically evaluated family members, 9 were affected by ET). | Lack of association with ETM1 | [35] |
| Italy | ETM1 (FET1) | 3q13 | 190300/2111 | Linkage analysis for ETM1, ETM2, and ETM3 in a large family with autosomal-dominant ET involving 6 generations | Lack of association with ETM1 | [36] |
| United States of America | ETM2 | 2p25-p22 | 602134/2112 | Linkage analysis in a large American-Czech family with “pure” autosomal-dominant ET (138 members, with 18 affected with ET; genetic anticipation over generations) | This gene was mapped close to D2S272 at chromosome 2p25-p22 (maximum LOD score = 5.92). Affected relatives showed a CAG repeat expansion not clearly located in the ETM2 locus. |
[30] |
| United States of America | ETM2 | 2p25-p22 | 602134/2112 | Linkage analysis in the previous large American-Czech family with “pure” autosomal-dominant ET and in 3 additional, unrelated American families using fine mapping results in an “only-affected” model | Positive combined pairwise LOD scores (Z) at the ETM2 locus with a Z(max) = 5.94 at a recombination fraction (theta) = 0.00 for locus D2S220. Haplotype reconstruction places the ETM2 gene in a 9.10 cM interval (D2S224-D2S405) Multipoint linkage analysis suggested that the ETM2 gene was a the 2.18 cM interval (D2S2150 and D2S220; Z(max) = 8.12). |
[37] |
| United States of America | ETM2 | 2p25-p22 | 602134/2112 | Linkage disequilibrium study involving 45 patients with familial ET and 70 normal controls (n = 70). Identification of 3 unreported dinucleotide polymorphic loci designated as etm1240, etm1231, and etm1234 in the ETM2 gene and haplotype analysis |
Significant differences in the allele frequencies between ET and controls of etm1231 (p = 0.0419) and etm1234 (p < 0.0001) loci. Significantly higher frequency of the A haplotype formed by the loci etm1231 and etm1234 in ET patients than in controls (29% vs. 9%) |
[38] |
| United States of America | ETM2 | 2p25-p22 | 602134/2112 | Linkage disequilibrium study involving 52 Singaporean patients with familial ET and 49 Singaporean normal controls (n = 70). Analysis of 6 polymorphic loci (etm1240, etm1231, etm1234, APOB, etm1241, and etm1242) in a 274 kb interval within an ET gene candidate region (ETM2), including haplotype analysis. |
Significant differences in the allele frequencies between cases and controls for the loci etm1234 (p = 0.0001) and APOB (p = 0.0320). Significantly higher frequency of a haplotype formed by the loci etm1231, etm1234, and APOB in ET patients than in controls (31% vs. 1.8%, p = 0.0005). |
[39] |
| United States of America | ETM2 | 2p25-p22 | 602134/2112 | Assembling of a physical map of the region between D2S224 and D2S2221 in the ETM2 locus by using high-throughput non-isotopic screening of bacterial artificial chromosomes (BACs), and construction of a complementary integrated physical map of the human ETM2 identifying GenBank contigs that contained seven BAC DNA sequences and common STSs. | Identification of 33 transcripts including five known genes (MATN3, LAPTM4A, SDC1, PUM2, and APOB) in this minimal critical region. | [40] |
| United States of America | ETM2 | 2p25-p22 | 602134/2112 | Linkage analysis with microsatellite markers for ETM1, ETM2, and chromosome 4p in 38 members of a six-generation family with ET | Lack of association with ETM2 and with chromosome 4p | [33] |
| Russia | ETM2 | 2p25-p22 | 602134/2112 | Linkage analysis for ETM1 and ETM2 loci, and for locus DYT1 on chromosome 9q32-34 in a group of Slavonic (11 patients) and Tajik (19 patients) families with ET. | Lack of association with DYT1 and ETM2 loci. | [34] |
| Korea | ETM2 | 2p25-p22 | 602134/2112 | Genetic association with 3 polymorphic loci (STS-etm1240, STS-etm1231, and STS-etm1234) located in a region of the ETM2, in 30 ET patients and 30 controls. | Detection of 8 different sequence variants (5 at etm1234, 2 at etm1240, and 1 at etm1231) in 7 patients (only in patients with “classic ET”). Decrease in the number of short tandem repeats within etm1234 locus more frequently in ET patients than in controls. |
[41] |
| Italy | ETM2 | 2p25-p22 | 602134/2112 | Linkage analysis for ETM1, ETM2, and ETM3 in a fifth-generation Italian kindred with autosomal-dominant ET (22 clinically evaluated family members, 9 were affected by ET). | Lack of association with ETM2 locus | [35] |
| Italy | ETM2 | 2p25-p22 | 602134/2112 | Linkage analysis for ETM1, ETM2, and ETM3 in a large family with autosomal-dominant ET involving 6 generations | Lack of association with ETM2 locus | [36] |
| Czech Republic | ETM2 | 2p25-p22 | 602134/2112 | Genetic analysis of 3 polymorphic loci (etm1231, etm1234, and etm1240), located within the ETM2 locus, in 61 Czech patients with familial ET and 68 healthy controls. | Lack of association with ETM2 locus | [42] |
| United States of America | ETM3 | 6p23 | 611456/101027378 | Genome-wide linkage screening and fine mapping in seven large North American families (325 individuals, 65 of them with definite ET). | Linkage to a locus on chromosome 6p23 in a family. A second family showed linkage to the same 6p23 region with a maximal NPL score 2.125 (p = 0.0075) and LOD score 1.265. Haplotype analysis led to the identification of a 600 kb interval shared by both families. Sequencing of 15 candidate genes located within this region did not find any sequence variants with pathogenic significance |
[31] |
| Italy | ETM3 | 6p23 | 611456/101027378 | Linkage analysis for ETM1, ETM2, and ETM3 in a fifth-generation Italian kindred with autosomal-dominant ET (22 clinically evaluated family members, 9 were affected by ET). | Lack of association with ETM3 | [35] |
| Italy | ETM3 | 6p23 | 611456/101027378 | Linkage analysis for ETM1, ETM2, and ETM3 in a large family with autosomal-dominant ET involving 6 generations | Lack of association with ETM3 | [36] |
| United States of America | No specific name | 5q35 | - | Linkage analysis using an affected-only dominant model involving 48 ET patients who belonged to 5 large ET pedigrees. Identification of genome segments followed by exome sequencing in pedigrees showing evidence of linkage. | One family showed genome-wide significant linkage to ET in chromosomes 5 and 18, but shared segment analysis reduced the 5q35 region by 1 Mb, and excluded the 18p11 candidate region. No causative variants in the 5q35 region were identified after exome sequencing. |
[32] |