Table 2.
Mutations previously hidden from standard genetic techniques but resolved after long-read sequencinga.
| Gene locus (PubMed and cochrane identifier) | Disorder | Mutation | Atypical features |
|---|---|---|---|
| ATXN10 | PD | ATTCC repeat expansion without ATTCC repeat interruptions (26) | Young-onset parkinsonism, normal brief smell identification test, mild cerebellar atrophy |
| SCA10 | ATTCT repeat expansion with ATTCC, ATCCT and ATCCC very-long repeat interruptions (25, 26, 41) | Focal motor seizures with impaired awareness 10–30 years after ataxia onset in patients with ATTCC repeat interruptions | |
| CLN6 | PME | 12.4 Kb deletion within a GC-rich region, and altering the gene's initiation codon (42) | Severe phenotype with regression, progressive diffuse atrophy and thin corpus callosum |
| CR1 | AD | Ten-nucleotide frameshift deletion in one of exons 10, 18 or 26 (43) | Two patients were first-degree relatives |
| C9ORF72 | ALS/FTD | GGGGCC repeat expansion (32, 44–47) | No |
| DMD | BMD phenotype | Acquisition of a new exon from the retrotransposable element LINE-1 (48) | No |
| DMD phenotype | Complex structural variants: 7 Kb to 0.9 Mb inversions flanked by 0.1–3.8 Kb deletion-insertion rearrangements (49, 50). SVs of breakpoint sequences with repetitive regions in intron 44 (51) | No | |
| DMPK | DM1 | CTG repeat expansion stabilization/contraction associated with de novo CCG repeat interruptions (52–54) | Milder symptoms in patients with CCG repeat interruptions |
| DPP6 | AD | Paracentric inversion of 4 Mb with the distal breakpoint in intron 1 of DPP6, disrupting its coding sequence (55) | Family with autosomal-dominant early-onset AD and with segregation of the mutation haplotype |
| DUX4 | FSHD | Contraction of the subtelomeric macrosatellite repeat D4Z4 (56, 57) | No |
| FMR1 | FXS/FXTAS | CGG repeat expansion with and without AGG repeat interruptions (58–61). Different FMR1 mRNA isoforms expressed (62) | Women with 60–85 CGG repeat expansions and higher AGG repeat interruptions were associated with to fewer chances of having children with FXS (expansion stabilization/contraction) |
| GBA | PD | 55-bp exonic deletion with a pathogenic p.D448H missense mutation (39) | Not specified |
| GIPC1 | OPDM2 | CGG repeat expansion (63, 64)a | No |
| LRP12 | OPDM1 | CGG repeat expansion (64) | No |
| MARCH6 | FAME3 | TTTCA/TTTTA repeat expansion (65) | No |
| MIR222 | X-linked intellectual disability | Two consecutive (CT)n and (GT)n repeat expansion (XLID25 repeat) (66) | No |
| NOTCH2NLC | ET | GGC repeat expansion (67, 68) | More severe phenotype, genetic anticipation, and few patients with other symptomsb |
| Hereditary distal motor neuropathy and rimmed vacuolar myopathy | GGC repeat expansions (69) | Rest and postural tremor in both hands, mildly high signal of the splenium of corpus callosum | |
| MSA | GGC repeat expansion (70) | Longer disease duration (>8 years), prominent cognitive impairment, mild-to-moderate cortical atrophy and mild white matter lesions | |
| NIID | GGC repeat expansion with and without GGA repeat interruptions (71–74). Also, CGG repeat expansion (75) | No | |
| OPDM3 | GGC repeat expansions (76) | White matter hiperintensities | |
| PD | GGC repeat expansion without GAA repeat interruptions but with or without AGC repeat interruptions (77) | Typical PD responsive to small dosages of levodopa (150–300 mg) for 10–20 years without motor fluctuations, and with mild cerebral atrophy | |
| Recurrent encephalopathy, postural tremor and parkinsonism | GGC repeat expansion (68) | Migraine, reversible focal neurological deficits, status epilepticus. DaTScan normal. Multifocal cortical and subcortical signal abnormalities without hyperintensity in corticomedullary junction in DWI. | |
| RAPGEF2 | FAME7 | TTTTA/TTTCA/TTTTA repeat expansion (78) | No |
| RFC1 | CANVAS | AAGGG repeat insertion (79) | Auditory hallucinations |
| SAMD12 | FAME1 | Three possible configurations of repeat expansions: TTTTA/TTTCA, TTTTA/TTTCA/TTTTA and TTTTA/TTTGA/TTTCA (42, 65, 78, 80–85) | No |
| SAMD9L | APS | Two distant, paternally inherited missense mutations p.R359Q and p.Y1118C (86) | Severe immune dysregulation, raised CSF protein levels, cerebellar atrophy and extensive supratentorial gray and white matter signal changes |
| STARD7 | FAME2 | ATTTC repeat expansion (87) | No |
| TAF1 | X-linked dystonia-parkinsonism | CCCTCT repeat expansion within the SINE-VNTR-Alu retrotransposon insertion (88) | No |
| TNRC6A | FAME6 | TTTTA/TTTCA/TTTTA repeat expansion (78) | No |
| YEATS2 | FAME4 | TTTCA/TTTTA repeat expansion (89) | No |
| Future studies | |||
| ClinicalTrials.gov Identifier | Study population | Gene loci | Objectives |
| NCT04621422c | Patients carrying mutations on selected genes | FMR1, DMPK, ZNF9, SCA2, JPH3, HD, FXN, C9ORF72, RFC1 | Compare repeat amplification results between Next Generation Oxford sequencing and reference PCR techniques |
Reference (63) reports the repeat expansion “GGC” which should have been named “CGG,” applying the HGVS 3' rule.
Cognitive impairment, frequent urination, hypermyotonia, ataxia, pyramidal signs, peripheral neuropathy or paroxysmal loss of consciousness.
Study not yet recruiting disclosed to analyze already existing biological collections from patients carrying the specified mutations.
AD, Alzheimer's Disease; ALS/FTD, amyotrophic lateral sclerosis/frontotemporal lobar degeneration; APS, Ataxia-pancytopenia syndrome; BMD, Becker muscular dystrophy; CANVAS, cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome; CSF, cerebrospinal fluid; DMD, Duchenne muscular dystrophy; DM1, myotonic dystrophy type-1; ET, essential tremor; FAME1, familial adult myoclonic epilepsy type 1; FSHD, facioscapulohumeral muscular dystrophy; FXS, Fragile X syndrome; FXTAS, fragile X tremor/ataxia syndrome; GD, Gaucher's disease; HD, Huntington Disease; MSA, multiple system atrophy; NIID, neuronal intranuclear inclusion disease; OPDM1, oculopharyngodistal myopathy type 1; PD, Parkinson's disease; PME, progressive myoclonus epilepsy; SCA10, spinocerebellar ataxia type 10; SVs, structural variants.