Table 1

Repeat expansion disorders associated with neurological disease

Disease	Gene	Repeat motif	Normal range	Pathogenic repeat number	Location	Inheritance	Phenotype
Spinocerebellar ataxia 1	ATXN1	CAG	6–39	>39	Exon	AD	Ataxia, neuropathy, pyramidal signs
Spinocerebellar ataxia 2	ATXN2	CAG	15–29	>34	Exon	AD	Ataxia, neuropathy, slow saccades, cognitive impairment, Cuban founder effect
Spinocerebellar ataxia 3	ATXN3	CAG	13–36	55–84	Exon	AD	Ataxia, pyramidal and extrapyramidal signs, large, Portuguese founder effect
Spinocerebellar ataxia 4	ZFHX3	GGC	<21–30	>48	Exon	AD	Ataxia, sensory axonal neuropathy, Swedish founder effect
Spinocerebellar ataxia 6	CACNA1A	CAG	4–16	21–30	Exon	AD	Slowly progressive ‘pure’ ataxia
Spinocerebellar ataxia 7	ATXN7	CAG	3–35	34 to >300	Exon	AD	Ataxia, visual loss with retinopathy
Spinocerebellar ataxia 8	ATXN8/ATXN8OS	CAG	6–37	~107–250	3'UTR	AD	Ataxia, slowly progressive, sensory neuropathy
Spinocerebellar ataxia 10	ATXN10	ATTCT	10–29	280–4500	Intron	AD	Ataxia, seizures
Spinocerebellar ataxia 12	PPP2R2B	CAG	<66	>66	5'UTR	AD	Ataxia, action tremor, hyper-reflexia, extrapyramidal features
Spinocerebellar ataxia 17	TBP	CAG	25–44	45–66	Exon	AD	Ataxia, chorea, dystonia, myoclonus, epilepsy
Spinocerebellar ataxia 27B	FGF14	GAA	6–249	>300	Intron	AD	Late-onset ataxia, may have episodic onset, downbeat nystagmus, vertigo, neuropathy
Spinocerebellar ataxia 31	BEAN1	TGGAA	NA (as insertion)	>500	Intron	AD	Late-onset ataxia, Japanese founder effect
Spinocerebellar ataxia 36	NOP56	GGCCTG	3–8	1500–2500	intron	AD	Ataxia, eye movement abnormalities, tongue fasciculations, upper motor neuron signs
Spinocerebellar ataxia 37	DAB1	ATTTC	NA (as insertion)	Insertion	5'UTR	AD	Slowly progressive gait and limb ataxia, eye movement abnormalities, dysphagia
Spinocerebellar ataxia 51	THAP11	CAG	19–39	45–100	Exon	AD	Late-onset ataxia, described in 2 Chinese families
Dentatorubral-pallidoluysian atrophy	ATN1	CAG	7–25	>49	Exon	AD	Ataxia, chorea, dementia, myoclonus, seizure, anticipation, common in Japan
Cerebellar ataxia, neuropathy and vestibular areflexia syndrome	RFC1	AAGGG	AAAAG:11–200, AAAGG 40–1000	AAGGG 400- >2000 Different motifs	Intron	AR	Late-onset ataxia, sensory neuropathy, vestibular areflexia syndrome
Friedreich’s ataxia	FXN	GAA	7–22	>66	Intron	AR	Ataxia, scoliosis, bladder dysfunction, absent lower-limb reflexes, and loss of position and vibration sense, cardiomyopathy, diabetes (later onset in 25%)
Fragile X-associated tremor/ataxia syndrome	FMR1	CGG	6–52	55–200	5'UTR	X-linked	Late-onset ataxia, intention tremor, followed by cognitive impairment
Fragile X syndrome	FMR1	CGG	6–52	>200	5'UTR	X-linked	Developmental delay, learning disability, autism spectrum disorder
Fragile-XE syndrome	FMR2/AFF2	CCG	6–25	>200	5'UTR	X-linked	Learning difficulty
Unverricht-Lundborg disease	CSTB	CCCCGCCCCGCG	2–3	>30	5'UTR	AR	Progressive myoclonic epilepsy type 1, Ataxia develops later
Neuronal intranuclear inclusion disease	NOTCH2NLC	GGC	<55	>55	5'UTR	AD	Clinical heterogeneous, cognitive impairment, movement disorder, prevalent in East Asians
X-linked dystonia parkinsonism	TAF1	CCCTCT	NA	30–55	Intron	X-linked	Dystonia, parkinsonism, founder effect within Filipino population
C9orf72-associated ALS/FTD	C9orf2	GGGGCC	<30	>500	Intron	AD	Pure frontotemporal dementia, pure amyotrophic lateral sclerosis or combination of the two
Huntington’s disease	HTT	CAG	6–34	36–180	Exon	AD	Progressive motor, cognitive, psychiatric disturbance
Huntington disease-like 2	JPH3	CAG/CTG	<50	>50	Exon	AD	Progressive movement disorder (including chorea, rigidity) with cognitive impairment. Common in African populations
Familial adult myoclonic epilepsy 1	SAMD12	TTTCA	NA (as insertion)	>149	Intron	AD	Adult-onset cortical myoclonus, with seizures in up to a half of patients
Familial adult myoclonic epilepsy 2	STARD7	ATTTC	NA (as insertion)	>274	Intron	AD	Finger, hand tremor with later-onset myoclonus and generalised tonic-clonic seizures
Familial adult myoclonic epilepsy 3	MARCHF6	TTTCA	NA (as insertion)	>600	Intron	AD	Adult-onset cortical tremor with epilepsy
Familial adult myoclonic epilepsy 4	YEATS2	TTTTA/ TTCA	NA (as insertion)	>829 or >221	Intron	AD	Adult-onset cortical tremor with epilepsy
Familial adult myoclonic epilepsy 6	TNRC6A	TTTCA	NA (as insertion)	Insertion	Intron	AD	Adult-onset myoclonic epilepsy
Familial adult myoclonic epilepsy 7	RAPFEG2	TTTCA	NA (as insertion)	Insertion	Intron	AD	Adult-onset myoclonic epilepsy
Myotonic dystrophy type 1	DMPK	CTG	5–37	>50 to ~2000	3'UTR	AD	Mild: cataracts, mild myotonia. Classic: weakness, myotonia, cataracts, cardiac abnormalities. Congenital: hypotonia, severe weakness at birth, respiratory difficulties.
Myotonic dystrophy type 2	CNBP/ZNF9	CCTG	<27	>75 to ~11 000	Intron	AD	Myotonia, weakness, cardiac conduction abnormalities, cardiomyopathy, insulin resistance, cataracts, hypogammaglobulinaemia
Oculopharyngeal muscular dystrophy	PABPN1	GCG	<10	>12–17	Exon	AD	Ptosis and dysphagia
Oculopharyngeal myopathy with leukoencephalopathy	NUTM2B-AS1	CGG	3–16	40–60	5'UTR	AD	Ptosis, ophthalmoplegia, dysphagia, dysarthria
Oculopharyngodistal myopathy 1	LRP12	CGG	13–45	90–130	5'UTR	AD	Adult-onset ptosis, ophthalmoplegia, facial, distal limb weakness, dysphagia
Oculopharyngodistal myopathy 2	GIPC1	CGG	12–32	97–120	5'UTR	AD	Slowly progressive distal weakness, ophthalmoplegia, facial and bulbar weakness
Kennedy’s disease (spinal and bulbar muscular atrophy)	AR	CAG	11–24	40–62	Exon	X-linked	Lower motor neurone and bulbar weakness. Androgen insensitivity: gynaecomastia, testicular atrophy

For mode of inheritance, AD, autosomal dominant and AR, autosomal recessive. ALS, amyotrophic lateral sclerosis; FTD, frontotemporal dementia. Phenotype and genotype descriptions, normal range and pathogenic range repeat sizes derived from Online Mendelian Inheritance in Man, GeneReviews and Bennett et al.39 Some of the repeat expansion disorders are insertional repeat expansions where the pathogenic repeat motif is not present in the reference genome or in unaffected individuals.