Table 1.
CMT cases diagnosed by WES in Neurology Laboratory, University of Crete
| Patient number | #1 | #2 | #3 |
|---|---|---|---|
| Sex | Male | Male | Male |
| Current age (years) | 66 | 19 | 44 |
| Age at symptom onset (years) | 50 | 2 | 17 |
| History/clinical features | Gait difficulties, atrophies and weakness of the lower and later the upper extremities | Gait difficulties, atrophies and weakness of the lower and later the upper extremities | Gait difficulties, atrophies and weakness of the lower and later the upper extremities |
| Additional clinical features | Parkinsonism | Hearing loss, dystonia | — |
| NCS/EMG features overviewa | Demyelinating type sensory motor neuropathy, resembling CIDP | Demyelinating type sensory motor neuropathy | Demyelinating type sensory motor neuropathy |
| Brain imaging features | Normal MRI findings, abnormal DATSCAN | Normal MRI findings | Few small foci of abnormal signal intensity at subcortical white matter of the cerebral hemispheres on MRI |
| Lumbar puncture results | 0 nucleated cells/μl, 85 mg/dl protein | 0 nucleated cells/μl, 46 mg/dl protein | Not performed |
| Additional diagnostic investigations | Nerve Ultrasound | — | — |
| Medical treatments tried | IV Ig, steroids | Botulinum toxin, levodopa (for dystonia) | — |
| Family history | Yes (brother with possible ALS) | Yes | No |
| Genetic tests performed before WES | PMP22 duplication | PMP22 duplication, CJB1 exon 2 sequencing | PMP22 duplication |
| Age at first diagnostic test—PMP22 duplication (y) | 55 | 13 | 36 |
| Age at diagnosis with WES (y) | 63 | 18 | 44 |
| Gene (OMIM number) | FIG4 (609390) | LITAF (603795) | GJB1 (304040) |
| Genetic variants (rs) | rs121908287, ‐ | rs104894522, | c.491G>A(rs1241595912) |
| HGVS nomenclature | NM_014845.5: c.122T>C; NP_055660.1: p.I41T/NM_014845.5: c.1795delC; NP_055660.1: p.H599fs*24 | NM_004862.3: c.364C>G; NP_004853.2: p.L122V | NM_000166.5: c.491G>A; NP_000157.1: p.R164Q |
| Variants (zygosity) | p.Ile41Thr (heterozygous)/p.His599Ilefs*24 (heterozygous) | p.Leu122Val (heterozygous) | p.Arg164Gln (hemizygous) |
| Functional consequence (Ingenuity Classification) | Pathogenic/pathogenic | Uncertain significance | Likely pathogenic |
| Functional consequence (ClinVar Classification) | Pathogenic/not reported | Pathogenic | Pathogenic |
| CADD score | 26.1/27.7 | 25.5 | 28.6 |
| Mode of inheritance | Autosomal recessive | Autosomal dominant | X‐linked dominant |
| CMT type (OMIM number) | 4J (611228) | 1C (601098) | X1 (302800) |
Abbreviations: ALS, amyotrophic lateral sclerosis; CADD, combined annotation‐dependent depletion (Rentzsch et al., 2018); CIDP, chronic inflammatory demyelinating polyneuropathy; CMT, Charcot–Marie–Tooth; EMG, electromyography; HGVS, Human Genome Variation Society; NCS, nerve conduction studies; WES, whole exome sequencing.
a
For details, see Table 2 and supplementary material.