TABLE 2.
Summary of clinical data of THOC2 variants with supporting molecular evidence.
| Individual | (likely) pathogenic | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | |||
| Variant details | c.2087C>T: p.Thr696Ile | c.2138G>A: p.Gly713Asp | c.3559C>T: p.His1187Tyr Twin 1 | c.3559C>T: p.His1187Tyr Twin 2 | Exon28: c.3503+4A>C | Exon35:c.4450-2A>G | c.1550A>G: p.Tyr517Cys | ||
| Gender | Male | Male | Male | Male | Male | Male | Female | ||
| Age (years) | 12 | 5 | 7 | 7 | 3 | 10 | 10 | ||
| Perinatal features | |||||||||
| Gestation (weeks) | 36 | 37 | 37 | 37 | 37 | 41 | NA | ||
| Low birth weight (<2.5kg) | Yes | No | Yes | Yes | No | No | NA | ||
| Birth weight (g) | 2000 | 2650 | 1990 | 2420 | 3018 | 4365 | NA | ||
| Neurologic features | |||||||||
| Intellectual disability | Severe | Mod+ | Mod+ | Mod+ | Severe | Severe | Profound | ||
| Speech delay | Yes, single words, signs | Yes, non-verbal | Yes | Yes | Yes, non-verbal | Yes, nasal dysarthria | Yes, non-verbal | ||
| Hypotonia | No | Yes | NA | NA | Yes | Yes, central hypotonia | Yes | ||
| Spasticity | No | No | No | No | No | Yes- appendicular spasticity | No | ||
| Hyperkinesia | No | No | Yes | Yes | Yes | No | No | ||
| Tremor | No | Yes, intermittent | No | No | No | Yes | No | ||
| Epilepsy | No | Suspected | No | No | No | No | Yes, epileptic encephalopathy | ||
| Gait disturbances | No | Yes, gait/balance problems | Yes, toe walking* | Yes, toe walking* | Non ambulatory | Yes, ataxia/broad based gait | Non ambulatory | ||
| Behaviour problems | No | Yes | Yes | Yes | Yes, ASD | No | NR | ||
| Anxiety | No | No | No | No | No | No | NR | ||
| Depression | No | No | No | No | No | No | NR | ||
| Brain MRI/CT | MRI normal | Thin corpus callosum, low brainstem volume, variability in gyral pattern. | ND | ND | Ventricular dilatation, delayed myelination, peri-ventricular white matter lesion | MRI within normal limits | MRI normal | ||
| Growth parameters | |||||||||
| Microcephaly (≤3%) | Yes | Yes,< 1% | No | No | No | Yes,2% | No, 5% | ||
| Short stature (≤3%) | Yes | Yes | No | No | No | No | No | ||
| Overweight (BMI≥25) | No | No | No | No | No | No | No | ||
| Broad high forehead | Yes | Yes | Yes | Yes | No | No | NR | ||
| Other features | Mild joint laxity, subluxed hips, disordered sleep, feeding difficulties (g-tube dependency), laryngomalacia, micrognathia, abnormal palmar creases | Noonan facies, pes planus, hypospadias | Noonan facies, pes planus, hypospadias | Clinodactyly, nystagmus, abnormality soft palate | Cortical visual impairment | ||||
Abbreviations: %, centile; ASD, autism spectrum disorder; CT, computerised tomography scan; g-tube, gastrostomy tube; mod+, at least moderate severity;
MRI, magnetic resonance imaging; ND, not done; NA, not available; NR, not reported; NICU, neonatal intensive care unit;
VOUS, variant of uncertain significance.
*
Toe walking in absence of neurological signs of lower limb spasticity, therefore considered a behavioural manifestation.