Table 2 Phenotype and pathogenic variants in affected index cases.
NR | PHENOTYPIC FEATURES | GENE & VARIANT | OMIM | INHERITANCE/ ZYGOSITY | ACMG CLASSIFICATION and CRITERIA | PRECISION THERAPY | THERAPY IMPLEMENTED OR ADJUSTED |
|---|---|---|---|---|---|---|---|
1 | Muscle weakness of the face, neck flexors, and distal limbs. Subtle glove-and-stocking sensory changes, with normal nerve conduction studies. The family history suggested an autosomal dominant inheritance pattern. | NEB Deletion (Exons 14-77) Variation ID: 831138 SCV001195028.1 | # 161650 | Autosomal Dominant Heterozygous | Pathogenic | None | Treatment is predominantly rehabilitative and symptomatic, as there are currently no effective disease-modifying therapies to alter its natural progression. |
2 | The clinical presentation is consistent with a suspected diagnosis of retinal vasculopathy and cerebral leukoencephalopathy with systemic manifestations (RVCL-S). | TREX1 NM_033629.6 Exon 2, c.795_802dup (p.Arg268Lysfs*12) Variation ID: 1463131 SCV002245235.1 | # 192315 | Autosomal Dominant Heterozygous | Likely Pathogenic PVS1 PM2 | Currently, a pilot study for treating RVCL-S with aclarubicin has been started. | Treatment is predominantly rehabilitative and symptomatic, as there are currently no effective disease-modifying therapies to alter its natural progression. |
3 | Early onset and slowly progressive muscle weakness. No Neuroimaging. | TTN NM_001267550.2: c.63577dup (p.Arg21193fs) Variation ID: 1506927 SCV002287929.4 | # 603689 | Autosomal Dominant Heterozygous | Likely pathogenic PVS1 PM2 PP5 | None | At present no disease-modifying therapy exists. Management is supportive. |
4 | Progressive proximal weakness in both the lower and upper limbs. EMG showed myopathic features. No Neuroimaging. | GAA NM_000152.5: c.-32-13T>G (Intronic) Variation ID: 4027 SCV000626604.10 | # 232300 | Autosomal Recessive Compound Heterozygous | Pathogenic PM3 PM2 BP7 PP5 | Enzyme replacement therapy is currently the most reliable treatment | Enzyme replacement therapy started. |
GAA NM_000152.5: c.1441T>C (p.Trp481Arg) Variation ID: 189007 SCV000956690.7 | Pathogenic PM3 PS3 PS1 PM1 PP2 PM2 PP3 PP5 | ||||||
5 | Delayed onset of walking, frequent falls and progressive limb weakness (distal > proximal). Nerve conduction studies: Sensorimotor polyneuropathy with mixed demyelinating and axonal features. No Neuroimaging. | MORC2 NM_001303256.3: c.707A>G (p.Glu236Gly) Variation ID: 254251 SCV000655832.8 | # 616688 | Autosomal Dominant Heterozygous | Pathogenic PS4 PM2 PM5 PP2 PP5 | None | Treatment is predominantly rehabilitative and symptomatic, as there are currently no effective disease-modifying therapies to alter its natural progression. |
6 | Lower limb weakness and spasticity, with a similarly affected sibling. No Neuroimaging. | SPG11 NM_025137.4: c.2612dup (p.Ser871fs) Variation ID: 856716 SCV001227014.6 | # 604360 | Autosomal Recessive Compound Heterozygous | Pathogenic PM3 PVS1 PM2 PP5 | None | At present, there is no specific treatment to prevent or reverse nerve degeneration in Hereditary Spastic Paraplegia. |
SPG11 NM_025137.4: c.5989_5992del (p.Leu1997fs) Variation ID: 41335 SCV001394007.6 | Pathogenic PM3 PP1 PVS1 PM2 PP5 | ||||||
7 | Progressive weakness and spasticity of the hands and lower limbs. No Neuroimaging. | SPG11 NM_025137.4: c.2716del (p.Gln906fs) Variation ID: 41297 SCV002188001.4 | # 604360 | Autosomal Recessive Compound Heterozygous | Pathogenic PM3 PVS1 PM2 PP5 | None | At present, there is no specific treatment to prevent or reverse nerve degeneration in Hereditary Spastic Paraplegia. |
SPG11 NM_025137.4: c.3997A>T (p.Lys1333Ter) Variation ID: 1456680 SCV002243137.4 | Pathogenic PVS1 PM2 PP5 | ||||||
8 | Progressive distal weakness in all limbs, dysarthria, nasal speech, and mild scapular winging. Normal ECG. | MYOT NM_006790.3: c.116C>T (p.Ser39Phe) Variation ID: 5839 SCV003439235.3 | # 609200 | Autosomal Dominant Heterozygous | Pathogenic PS4 PP1 PM2 PP5 | None | Treatment is predominantly rehabilitative and symptomatic, as there are currently no effective disease-modifying therapies to alter its natural progression. |
9 | Congenital limb contractures, progressive motor decline and loss of ambulation in early childhood. Normal Neuroimaging. | COL6A2 NM_001849.4: c.802-2A>G (Splice acceptor) Variation ID: 290251 SCV003232417.3 | # 620725 | Autosomal Dominant Heterozygous | Likely pathogenic PVS1 PM2 PP5 | None | Treatment is predominantly rehabilitative and symptomatic, as there are currently no effective disease-modifying therapies to alter its natural progression. |
10 | Progressive muscle weakness with loss of ambulation. A similarly affected sibling. Creatine kinase levels significantly elevated. No Neuroimaging. | DYSF NM_001130987.2: c.5458-1G>A (Splice acceptor) Variation ID: 284470 SCV001574048.5 | # 253601 | Autosomal Recessive Homozygous | Pathogenic PM3 PVS1 PM2 PP5 | None | There is no approved therapy for dysferlinopathy. Treatment is symptomatic only. |
11 | Cardiomyopathy and arrhythmia, with bilateral proximal weakness of the lower limbs and right scapular weakness. No Neuroimaging. | DMD Gain (Exons 2-7) Variation ID: 455821 SCV000625794.9 | # 300376 | X - Linked Hemizygous | Pathogenic HI SCORE:3 Sufficient Evidence for Haploinsufficiency | Dystrophin Restoration Therapies | Treatment of Cardiomyopathy and scoliosis. Corticosteroid therapy to treat weakness. |
12 | Progressive muscle weakness affecting the limb-girdle musculature of the lower limbs. No Neuroimaging. | CAPN3 NM_000070.3: c.1117T>C (p.Trp373Arg) Variation ID: 217145 SCV000645464.6 | # 253600 | Autosomal Recessive Homozygous | Pathogenic PS4 PP1 PS3 PM2 PP2 PP3 PP5 | None | Treatment is predominantly rehabilitative and symptomatic, as there are currently no effective disease-modifying therapies to alter its natural progression. |
13 | Distal weakness with an autosomal dominant inheritance pattern. No Neuroimaging. | PMP22 Gain (Entire coding sequence) Variation ID: 218289 SCV000219138.4 | # 118220 | Autosomal Dominant Heterozygous | Pathogenic HI SCORE:3 Sufficient Evidence for Haploinsufficiency | None | Treatment is predominantly rehabilitative and symptomatic, as there are currently no effective disease-modifying therapies to alter its natural progression. |
14 | Myotonia involving limbs and facial muscles. EMG confirmed frequent myotonic discharges. No Neuroimaging. | CLCN1 NM_000083.3: c.1437_1450del (p.Pro480fs) Variation ID: 279778 SCV000636291.10 | # 255700 | Autosomal Recessive Compound Heterozygous | Pathogenic PM3 PVS1 PM2 PP5 | None | Myotonic stiffness may respond to sodium channel blockers or other pharmacologic treatment options. |
CLCN1 NM_000083.3: c.1580T>G (p.Ile527Ser) Variation ID: 860935 SCV001232393.6 | Pathogenic PM3 PP3 PM2 PM5 PP2 PP5 | ||||||
15 | Cerebral hemorrhaging and progressive cognitive decline. A similarly affected parent suggested an autosomal dominant inheritance. No Neuroimaging. | APP NM_000484.4: c.2077G>C (p.Glu693Gln) Variation ID: 18087 SCV001587274.5 | # 605714 | Autosomal Dominant Heterozygous | Pathogenic PS4 PP1 PS3 PM2 PM1 PM5 PP3 PP5 | None | Management is often based on presenting symptoms. |
16 | Neuropathy, ataxia, and vision loss. A positive family history was noted. No Neuroimaging. | AIPL1 NM_014336.5: c.834G>A (p.Trp278Ter) Variation ID: 5565 SCV000833757.7 | # 604393 | Autosomal Recessive Homozygous | Pathogenic PM3 PP1 PS3 PVS1 PM2 PP5 | Successful gene supplementation therapy in experimental models of AIPL1 - associated LCA. | Management is symptomatic. |
17 | Gait difficulties, with involvement of both proximal and distal muscle groups with dysphagia. Central core myopathy on muscle biopsy. | MYH7 NM_000257.4: c.4850_4852del (p.Lys1617del) Variation ID: 190401 SCV000623724.7 | # 160500 | Autosomal Dominant Heterozygous | Pathogenic PS4 PP1 PM2 PM4 PM1 PP5 | None | Treatment is predominantly rehabilitative and symptomatic, as there are currently no effective disease-modifying therapies to alter its natural progression. |
