Table 2.
List of noncoding repeat expansion disorders involving motifs up to 12 nucleotides, sorted according to their year of discovery
| ID year | Disordera | Inheritanceb | Chr | Gene | Location | Repeat motif | pathogenic motif when different | Normal repeat range | Pathological repeat range | Pathological mechanism(s)c | ID methodd | Ref |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1991 | FXS | XLD | Xq27.3 | FMR1 | 5′ UTR | CGG | – | 5–50 | >200 | Me/GS | K, FS, L, Me, cl | Oberlé et al.,8 Verkerk et al.9 |
| 1992 | DM1 | AD | 19q13.32 | DMPK | 3′ UTR | CTG | – | 5–37 | >50–10,000 | RNA (foci, PS), RAN (polyQ) | L, cl | Mahadevan et al.31 |
| 1993 | FRAXE | XLR | Xq28 | AFF2 | 5′ UTR | CCG | – | 4–39 | ≥200–900 | Me/GS | K, L | Knight et al.32 |
| 1996 | FRDA | AR | 9q21.11 | FXN | intron | GAA | – | 5–34 | ≥66–1300 | EGS | L, ExScr | Campuzano et al.33 |
| 1997 | EPM1 | AR | 21q22.3 | CSTB | promoter / 5′ UTR | CCCCGCCCCGCG | – | 2–3 | ≥30–75 | EGS | L, cl, exp | Lalioti et al.34 |
| 1998 | FXPOI | XL | Xq27.3 | FMR1 | 5′ UTR | CGG | – | 5–50 | 55–200 | RNA (foci), RAN | Fam, ExScr | Conway et al.35 |
| 1999 | SCA8 | AD | 13q21 | ATXN8 / ATXN8OS | 3′ UTR | CAG/CTG | – | 15–50 | >74–250 | RNA (foci), RAN | L, cl | Koob et al.36 |
| 1999 | SCA12 | AD | 5q31 | PPP2R2B | 5′ UTR | CAG | – | 4–32 | ≥43–78 | RAN (polyG)? | L, RED | Holmes et al.37 |
| 2000 | SCA10 | AD | 22q13 | ATXN10 | intron | ATTCT / ATTGT | – | 10–32 | >280–4,500 | RNA (foci) | L, ExScr | Matsuura et al.38 |
| 2001 | DM2 | AD | 3q21.3 | CNBP | intron | CCTG / CAGG | – | 11–30 | >50−11,000 | RNA (foci) | L, ExScr | Liquori et al.39 |
| 2001 | FXTAS | XLR | Xq27.3 | FMR1 | 5′ UTR | CGG | – | 5–50 | 55–200 | RNA (foci), RAN (polyG) | Fam | Hagerman et al.40 |
| 2009 | SCA31 | AD | 16q22 | BEAN1 / TK2 | intron | TAAAA | TGGAA (+TAGAA) | variable | ≥110–760 | RNA (foci, PS), RAN? | L | Sato et al.41 |
| 2011 | SCA36 | AD | 20p13 | NOP56 | intron | GGCCTG | – | 5–14 | ≥650–2,500 | RNA (foci) | L, ExScr | Kobayashi et al.42 |
| 2011 | FTD/ALS | AD | 9p21.2 | C9ORF72 | 5′ UTR / intron | GGGGCC | – | 3–25 | >30 | RNA (foci), RAN (polyG) | L, WGS | Renton et al.,43 DeJesus-Hernandez et al.44 |
| 2015 | FECD3 | AD | 18q21.2 | TCF4 | intron | CTG | – | 5–31 | >50 | unknown | L, GWAS | Mootha et al.45,46 |
| 2017 | XDP | XLR | Xq13.1 | TAF1 | intron (retrotransposon) | CCCTCT | – | none | 30–55 | unknown | L, exp | Bragg et al.47 |
| 2017 | SCA37 | AD | 1p32 | DAB1 | intron | ATTTT | ATTTC | 7-400 (ATTTT) | ≥31–75 ATTTC | RNA | L, ExScr | Seixas et al.48 |
| 2018 | FAME1 | AD | 8q24 | SAMD12 | intron | ATTTT | ATTTC | 7-exp (ATTTT) | ≥440–3,680 ATTTC | RNA? | L, ExScr | Ishiura et al.49 |
| 2018 | FAME6 | AD | 16p12.1 | TNRC6A | intron | ATTTT | ATTTC | N/A | N/A | RNA? | TRhist | Ishiura et al.49 |
| 2018 | FAME7 | AD | 4q32.1 | RAPGEF2 | intron | ATTTT | ATTTC | N/A | N/A | RNA? | TRhist | Ishiura et al.49 |
| 2019 | BSS | AR | 16p12.3 | XYLT1 | promoter | CGG | – | 9–20 | 120–800 | Me/GS | ADO, Me | LaCroix et al.50 |
| 2019 | CANVAS | AR | 4p14 | RFC1 | intron | AAAAG / AAAGG / AAGAG / AGAGG | AAGGG | variable | ≥400–2,000 | unknown | L, WGS | Cortese et al.,51 Rafehi et al.52 |
| 2019 | GDPAG | AR | 2q32.2 | GLS | 5′ UTR | GCA | – | 8–16 | ≥680–1,400 | EGS | CGA | van Kuilenburg et al.53 |
| 2019 | NIID | AD | 1q21.2 | NOTCH2NLC | 5′ UTR / exon 1 | CGG | – | 7–60 | ≥61–500 | Me/GS, RAN (polyG)? | TRhist, L, WGS | Ishiura et al.,54 Sone et al.,55 Tian et al.56 |
| 2019 | OPDM1 | AD | 8q22.3 | LRP12 | 5′ UTR | CGG | – | 13–45 | 90–130 | RAN (polyG)? | TRhist | Ishiura et al.54 |
| 2019 | OPML1 | AD | 10q22.3 | NUTM2B-AS1 | noncoding RNA gene | CGG/CCG | – | 3–16 | 40–60 | RAN (polyG)? | TRhist | Ishiura et al.54 |
| 2019 | FAME4 | AD | 3q27.1 | YEATS2 | intron | ATTTT | ATTTC | 7–400 (ATTTT) | N/A | RNA? | L, ExScr | Yeetong et al.57 |
| 2019 | FAME2 | AD | 2q11.2 | STARD7 | intron | ATTTT | ATTTC | 9–20 | ≥661–735 | RNA? | L, ExScr | Corbett et al.58 |
| 2019 | FAME3 | AD | 5p15.2 | MARCHF6 | intron | ATTTT | ATTTC | 10–30 | ≥660–2,800 | RNA? | L, ExScr | Florian et al.59 |
| 2020 | OPDM2 | AD | 19p13.12 | GIPC1 | 5′ UTR | CGG | – | 12–32 | ≥97–120 | unknown | L, WGS, LRS | Deng et al.60 |
ID, identification; chr, chromosome; N/A, not available; ref, reference(s); UTR, untranslated region
BSS, Baratela-Scott syndrome; CANVAS, cerebellar ataxia, neuropathy and vestibular areflexia syndrome; DM1, myotonic dystrophy type 1; DM2, myotonic dystrophy type 2; EPM1, progressive myoclonus epilepsy type 1 (Unverricht-Lundborg disease); FAME, familial adult myoclonic epilepsy; FECD3, Fuchs endothelial corneal dystrophy type 3; FRAXE, fragile XE syndrome; FRDA, Friedreich ataxia; FTD/ALS, frontotemporal dementia/amyotrophic lateral sclerosis; FXPOI, Fragile X-associated premature ovarian infertility; FXS, fragile X syndrome; FXTAS, fragile X-associated tremor ataxia syndrome; GDPAG, global developmental delay, progressive ataxia, and elevated glutamine; NIID, neuronal intranuclear inclusion disease; OPDM1, oculopharyngodistal myopathy type 1; OPDM2, oculopharyngodistal myopathy type 2; OPML1, oculopharyngeal myopathy with leukoencephalopathy type 1; SCA, spinocerebellar ataxia; XDP, X-linked dystonia parkinsonism
AD, autosomal dominant; XL, X-linked; XLR, X-linked, recessive; XLD, X-linked, dominant
EGS, epigenetic gene silencing; Me/GS, gene silencing associated with hypermethylation; PS, protein sequestration; RNA, RNA toxicity; RAN, repeat-associated non-AUG translation
ADO, allele drop-out; cl, cloning; CGA, candidate gene analysis; exp, expression; ExScr, expansion screening; Fam, clinical analyses in fragile X-affected families; FS, fragile site; GWAS, genome-wide association study; K, karyotyping; L, linkage; LRS, long-read sequencing; RED, repeat expansion detection; WGS, whole-genome sequencing