Focused exome sequencing identified pathogenic or likely pathogenic variants in known leukodystrophy/leukoencephalopathy genes in 26 cases (Table 1). The most frequently mutated genes were EIF2B4/5 causing vanishing white matter (VWM), CSF1R, causing adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), AARS2, causing a leukoencephalopathy with ovarian failure and NOTCH3, causing cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (Fig. 1). We detected variants of uncertain significance in POLR3A, MRPS22 and TNR in three patients (Supplementary material).
Table 1
Pathogenic and likely pathogenic variants detected in known leukodystrophy and leukoencephalopathy genes
| Patient ID | Gene | Variant | Predicted protein effect | Sex | AAO | Family history | Initial syndrome | Additional features |
|---|---|---|---|---|---|---|---|---|
| Vascular leukoencephalopathy | ||||||||
| P1 | NOTCH3 | c.505C > T | p.R169C | M | 30 | AD | Migraine with aura | Parietal ischaemic stroke |
| P2 | NOTCH3 | c.994C > T | p.R332C | M | 37 | AD | Recurrent TIA | Progressive gait deterioration, dysarthria, cognitive decline |
| P3 | NOTCH3 | c.397C > T | p.R133C | F | 36 | No | Migraine with aura | Ischaemic stroke, cognitive decline |
| P4 | NOTCH3 | c.1591T > G | p.C531G | F | 36 | AD | Prepontine SAH | Migraine with aura |
| P28 | CTSA | c.973C > T | p.R325C | F | 42 | AD | Migraine, hypertension | Mild cognitive decline, behavioural change |
| Vanishing white matter disease | ||||||||
| P5 | EIF2B4 | c.[495 + 3delA (;) 623G > A] | p.[? (;) R208Q] | F | 20 | AR | Epilepsy | Spastic tetraparesis, ataxia, cognitive decline |
| P6 | EIF2B5 | c.[338G > A];[380T > C] | p.[R113H];[L127P] | F | 53 | No | Cognitive decline | Migraine, ataxia, personality change |
| P7 | EIF2B5 | c.[338G > A];[913A > T] | p.[R113H];[M305L] | F | 52 | No | Trigeminal neuralgia | Temporal seizures, ataxia, cognitive decline |
| P8 | EIF2B5 | c.[338G > A];[338G > A] | p.[R113H];[R113H] | M | 31 | No | Slowly progressive hemiparesis | Cognitive decline, ataxia |
| P26 | EIF2B5 | c.[338G > A];[338G > A] | p.[R113H];[R113H] | M | 26 | No | Cognitive decline | Falls, parkinsonism |
| Hypomyelinating disorders | ||||||||
| P9 | PLP1 | c.276C > A | p.Y92* | F | 30 | AD/XLD | Spastic gait, ataxia | Executive dysfunction, impaired visual memory |
| P10 | PLP1 | c.355dupG | p.Q121Pfs*83 | M | 30 | No | Spastic gait, head tremor, | Executive dysfunction, cognitive decline, bladder/bowel disturbance |
| P12 | TUBB4A | c.G538G > A | p.V180M | F | Infancy | De novo | Spasticity, dystonia | Dysarthria, cognitive decline |
| Mitochondrial proteins | ||||||||
| P13 | DARS2 | c.[228‐20_-21 delTTinsC];[1433T > C] | p.[R76Sfs*5];[F479S] | M | 15 | No | LL weakness, neuropathy | Ataxia |
| P14 | DARS2 | c.[228‐20_-21 delTTinsC];[1456C > T] | p.[R76Sfs*5];[L486F] | F | 5 | No | Bilateral UL intention tremor, progressive gait impairment | Cognitive decline, spastic paraplegia, sensory ataxia |
| Genes involved in microglial signalling | ||||||||
| P16 | CSF1R | c.1901T > G | p.L634R | F | 53 | No | Ataxia, spasticity | Cognitive, dyspraxia |
| P17 | CSF1R | c.2570C > T | p.P857L | F | 38 | No | Spastic gait | Severe spastic tetraparesis, dystonia, cognitive decline |
| P18 | CSF1R | c.2381T > C | p.I794T | M | 52 | No | Cognitive decline | UL dyspraxia, alien limb, spasticity, parkinsonism |
| P27 | CSF1R | c.2345G > A | p.R782H | M | 46 | AD | Cognitive decline | Depression, apraxia |
| P19 | TREM2 | c.[377T > G];[377T > G] | p.[V126G];[V126G] | M | 25 | AR | Cognitive decline | Frequent generalized seizures |
| Miscellaneous | ||||||||
| P21 | RNF216 | c.[1482C > A];[1482C > A] | p.[Y494*];[Y494*] | M | 31 | Consang | Cognitive decline | Ataxia, hypogonadotrophic hypogonadism |
| Patient ID | Gene | Variant | Predicted protein effect | Sex | AAO | Family history | Initial syndrome | Additional features |
|---|---|---|---|---|---|---|---|---|
| Vascular leukoencephalopathy | ||||||||
| P1 | NOTCH3 | c.505C > T | p.R169C | M | 30 | AD | Migraine with aura | Parietal ischaemic stroke |
| P2 | NOTCH3 | c.994C > T | p.R332C | M | 37 | AD | Recurrent TIA | Progressive gait deterioration, dysarthria, cognitive decline |
| P3 | NOTCH3 | c.397C > T | p.R133C | F | 36 | No | Migraine with aura | Ischaemic stroke, cognitive decline |
| P4 | NOTCH3 | c.1591T > G | p.C531G | F | 36 | AD | Prepontine SAH | Migraine with aura |
| P28 | CTSA | c.973C > T | p.R325C | F | 42 | AD | Migraine, hypertension | Mild cognitive decline, behavioural change |
| Vanishing white matter disease | ||||||||
| P5 | EIF2B4 | c.[495 + 3delA (;) 623G > A] | p.[? (;) R208Q] | F | 20 | AR | Epilepsy | Spastic tetraparesis, ataxia, cognitive decline |
| P6 | EIF2B5 | c.[338G > A];[380T > C] | p.[R113H];[L127P] | F | 53 | No | Cognitive decline | Migraine, ataxia, personality change |
| P7 | EIF2B5 | c.[338G > A];[913A > T] | p.[R113H];[M305L] | F | 52 | No | Trigeminal neuralgia | Temporal seizures, ataxia, cognitive decline |
| P8 | EIF2B5 | c.[338G > A];[338G > A] | p.[R113H];[R113H] | M | 31 | No | Slowly progressive hemiparesis | Cognitive decline, ataxia |
| P26 | EIF2B5 | c.[338G > A];[338G > A] | p.[R113H];[R113H] | M | 26 | No | Cognitive decline | Falls, parkinsonism |
| Hypomyelinating disorders | ||||||||
| P9 | PLP1 | c.276C > A | p.Y92* | F | 30 | AD/XLD | Spastic gait, ataxia | Executive dysfunction, impaired visual memory |
| P10 | PLP1 | c.355dupG | p.Q121Pfs*83 | M | 30 | No | Spastic gait, head tremor, | Executive dysfunction, cognitive decline, bladder/bowel disturbance |
| P12 | TUBB4A | c.G538G > A | p.V180M | F | Infancy | De novo | Spasticity, dystonia | Dysarthria, cognitive decline |
| Mitochondrial proteins | ||||||||
| P13 | DARS2 | c.[228‐20_-21 delTTinsC];[1433T > C] | p.[R76Sfs*5];[F479S] | M | 15 | No | LL weakness, neuropathy | Ataxia |
| P14 | DARS2 | c.[228‐20_-21 delTTinsC];[1456C > T] | p.[R76Sfs*5];[L486F] | F | 5 | No | Bilateral UL intention tremor, progressive gait impairment | Cognitive decline, spastic paraplegia, sensory ataxia |
| Genes involved in microglial signalling | ||||||||
| P16 | CSF1R | c.1901T > G | p.L634R | F | 53 | No | Ataxia, spasticity | Cognitive, dyspraxia |
| P17 | CSF1R | c.2570C > T | p.P857L | F | 38 | No | Spastic gait | Severe spastic tetraparesis, dystonia, cognitive decline |
| P18 | CSF1R | c.2381T > C | p.I794T | M | 52 | No | Cognitive decline | UL dyspraxia, alien limb, spasticity, parkinsonism |
| P27 | CSF1R | c.2345G > A | p.R782H | M | 46 | AD | Cognitive decline | Depression, apraxia |
| P19 | TREM2 | c.[377T > G];[377T > G] | p.[V126G];[V126G] | M | 25 | AR | Cognitive decline | Frequent generalized seizures |
| Miscellaneous | ||||||||
| P21 | RNF216 | c.[1482C > A];[1482C > A] | p.[Y494*];[Y494*] | M | 31 | Consang | Cognitive decline | Ataxia, hypogonadotrophic hypogonadism |
AAO = age at onset; AD = autosomal dominant; AR = autosomal recessive; XLD = X-linked dominant; consang = consanguineous relationship; SAH = subarachnoid haemorrhage; TIA = transient ischaemic attack; UL = upper limb; LL = lower limb.
Table 1
Pathogenic and likely pathogenic variants detected in known leukodystrophy and leukoencephalopathy genes
| Patient ID | Gene | Variant | Predicted protein effect | Sex | AAO | Family history | Initial syndrome | Additional features |
|---|---|---|---|---|---|---|---|---|
| Vascular leukoencephalopathy | ||||||||
| P1 | NOTCH3 | c.505C > T | p.R169C | M | 30 | AD | Migraine with aura | Parietal ischaemic stroke |
| P2 | NOTCH3 | c.994C > T | p.R332C | M | 37 | AD | Recurrent TIA | Progressive gait deterioration, dysarthria, cognitive decline |
| P3 | NOTCH3 | c.397C > T | p.R133C | F | 36 | No | Migraine with aura | Ischaemic stroke, cognitive decline |
| P4 | NOTCH3 | c.1591T > G | p.C531G | F | 36 | AD | Prepontine SAH | Migraine with aura |
| P28 | CTSA | c.973C > T | p.R325C | F | 42 | AD | Migraine, hypertension | Mild cognitive decline, behavioural change |
| Vanishing white matter disease | ||||||||
| P5 | EIF2B4 | c.[495 + 3delA (;) 623G > A] | p.[? (;) R208Q] | F | 20 | AR | Epilepsy | Spastic tetraparesis, ataxia, cognitive decline |
| P6 | EIF2B5 | c.[338G > A];[380T > C] | p.[R113H];[L127P] | F | 53 | No | Cognitive decline | Migraine, ataxia, personality change |
| P7 | EIF2B5 | c.[338G > A];[913A > T] | p.[R113H];[M305L] | F | 52 | No | Trigeminal neuralgia | Temporal seizures, ataxia, cognitive decline |
| P8 | EIF2B5 | c.[338G > A];[338G > A] | p.[R113H];[R113H] | M | 31 | No | Slowly progressive hemiparesis | Cognitive decline, ataxia |
| P26 | EIF2B5 | c.[338G > A];[338G > A] | p.[R113H];[R113H] | M | 26 | No | Cognitive decline | Falls, parkinsonism |
| Hypomyelinating disorders | ||||||||
| P9 | PLP1 | c.276C > A | p.Y92* | F | 30 | AD/XLD | Spastic gait, ataxia | Executive dysfunction, impaired visual memory |
| P10 | PLP1 | c.355dupG | p.Q121Pfs*83 | M | 30 | No | Spastic gait, head tremor, | Executive dysfunction, cognitive decline, bladder/bowel disturbance |
| P12 | TUBB4A | c.G538G > A | p.V180M | F | Infancy | De novo | Spasticity, dystonia | Dysarthria, cognitive decline |
| Mitochondrial proteins | ||||||||
| P13 | DARS2 | c.[228‐20_-21 delTTinsC];[1433T > C] | p.[R76Sfs*5];[F479S] | M | 15 | No | LL weakness, neuropathy | Ataxia |
| P14 | DARS2 | c.[228‐20_-21 delTTinsC];[1456C > T] | p.[R76Sfs*5];[L486F] | F | 5 | No | Bilateral UL intention tremor, progressive gait impairment | Cognitive decline, spastic paraplegia, sensory ataxia |
| Genes involved in microglial signalling | ||||||||
| P16 | CSF1R | c.1901T > G | p.L634R | F | 53 | No | Ataxia, spasticity | Cognitive, dyspraxia |
| P17 | CSF1R | c.2570C > T | p.P857L | F | 38 | No | Spastic gait | Severe spastic tetraparesis, dystonia, cognitive decline |
| P18 | CSF1R | c.2381T > C | p.I794T | M | 52 | No | Cognitive decline | UL dyspraxia, alien limb, spasticity, parkinsonism |
| P27 | CSF1R | c.2345G > A | p.R782H | M | 46 | AD | Cognitive decline | Depression, apraxia |
| P19 | TREM2 | c.[377T > G];[377T > G] | p.[V126G];[V126G] | M | 25 | AR | Cognitive decline | Frequent generalized seizures |
| Miscellaneous | ||||||||
| P21 | RNF216 | c.[1482C > A];[1482C > A] | p.[Y494*];[Y494*] | M | 31 | Consang | Cognitive decline | Ataxia, hypogonadotrophic hypogonadism |
| Patient ID | Gene | Variant | Predicted protein effect | Sex | AAO | Family history | Initial syndrome | Additional features |
|---|---|---|---|---|---|---|---|---|
| Vascular leukoencephalopathy | ||||||||
| P1 | NOTCH3 | c.505C > T | p.R169C | M | 30 | AD | Migraine with aura | Parietal ischaemic stroke |
| P2 | NOTCH3 | c.994C > T | p.R332C | M | 37 | AD | Recurrent TIA | Progressive gait deterioration, dysarthria, cognitive decline |
| P3 | NOTCH3 | c.397C > T | p.R133C | F | 36 | No | Migraine with aura | Ischaemic stroke, cognitive decline |
| P4 | NOTCH3 | c.1591T > G | p.C531G | F | 36 | AD | Prepontine SAH | Migraine with aura |
| P28 | CTSA | c.973C > T | p.R325C | F | 42 | AD | Migraine, hypertension | Mild cognitive decline, behavioural change |
| Vanishing white matter disease | ||||||||
| P5 | EIF2B4 | c.[495 + 3delA (;) 623G > A] | p.[? (;) R208Q] | F | 20 | AR | Epilepsy | Spastic tetraparesis, ataxia, cognitive decline |
| P6 | EIF2B5 | c.[338G > A];[380T > C] | p.[R113H];[L127P] | F | 53 | No | Cognitive decline | Migraine, ataxia, personality change |
| P7 | EIF2B5 | c.[338G > A];[913A > T] | p.[R113H];[M305L] | F | 52 | No | Trigeminal neuralgia | Temporal seizures, ataxia, cognitive decline |
| P8 | EIF2B5 | c.[338G > A];[338G > A] | p.[R113H];[R113H] | M | 31 | No | Slowly progressive hemiparesis | Cognitive decline, ataxia |
| P26 | EIF2B5 | c.[338G > A];[338G > A] | p.[R113H];[R113H] | M | 26 | No | Cognitive decline | Falls, parkinsonism |
| Hypomyelinating disorders | ||||||||
| P9 | PLP1 | c.276C > A | p.Y92* | F | 30 | AD/XLD | Spastic gait, ataxia | Executive dysfunction, impaired visual memory |
| P10 | PLP1 | c.355dupG | p.Q121Pfs*83 | M | 30 | No | Spastic gait, head tremor, | Executive dysfunction, cognitive decline, bladder/bowel disturbance |
| P12 | TUBB4A | c.G538G > A | p.V180M | F | Infancy | De novo | Spasticity, dystonia | Dysarthria, cognitive decline |
| Mitochondrial proteins | ||||||||
| P13 | DARS2 | c.[228‐20_-21 delTTinsC];[1433T > C] | p.[R76Sfs*5];[F479S] | M | 15 | No | LL weakness, neuropathy | Ataxia |
| P14 | DARS2 | c.[228‐20_-21 delTTinsC];[1456C > T] | p.[R76Sfs*5];[L486F] | F | 5 | No | Bilateral UL intention tremor, progressive gait impairment | Cognitive decline, spastic paraplegia, sensory ataxia |
| Genes involved in microglial signalling | ||||||||
| P16 | CSF1R | c.1901T > G | p.L634R | F | 53 | No | Ataxia, spasticity | Cognitive, dyspraxia |
| P17 | CSF1R | c.2570C > T | p.P857L | F | 38 | No | Spastic gait | Severe spastic tetraparesis, dystonia, cognitive decline |
| P18 | CSF1R | c.2381T > C | p.I794T | M | 52 | No | Cognitive decline | UL dyspraxia, alien limb, spasticity, parkinsonism |
| P27 | CSF1R | c.2345G > A | p.R782H | M | 46 | AD | Cognitive decline | Depression, apraxia |
| P19 | TREM2 | c.[377T > G];[377T > G] | p.[V126G];[V126G] | M | 25 | AR | Cognitive decline | Frequent generalized seizures |
| Miscellaneous | ||||||||
| P21 | RNF216 | c.[1482C > A];[1482C > A] | p.[Y494*];[Y494*] | M | 31 | Consang | Cognitive decline | Ataxia, hypogonadotrophic hypogonadism |
AAO = age at onset; AD = autosomal dominant; AR = autosomal recessive; XLD = X-linked dominant; consang = consanguineous relationship; SAH = subarachnoid haemorrhage; TIA = transient ischaemic attack; UL = upper limb; LL = lower limb.
Figure 1
Pathogenic and likely pathogenic variants identified in known leukodystrophy/genetic leukoencephalopathy genes and coverage metrics for focused exome and WES.
