Table 1.
TUBB3-CFEOM variant phenotypes.
| NM_006086 | Variant | R62Q | S78T | R262C | E421D | D417N | D417H | E410V | E410K | R262H | A302T | R380C |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Nucleotide | 185G > A | 232 T > A | 784C > T | 1263G > C | 1249G > A | 1249G > C | 1229A > T | 1228G > A | 785G > A | 904G > A2 | 1138C > T | |
| Pedigree Information | # Pedigrees1 | 1 | 1 | 20 | 1 | 7 | 2 | 1 | 17 | 153 | 4 | 6 |
| # M/F/U/fetus | 1/1/0/0 | 1/1/0/0 | 50+/50+/0/0 | 3/0/0/0 | 12/7/1/0 | 2/4/0/0 | 1/0/0/0 | 12/8/0/0 | 10/5/1/0 | 2/5/0/0 | 3/1/2/1 | |
| Inheritance | AD | AD | AD>DN | AD | AD/DN | AD | DN | AD<DN | DN | AD/DN/G | DN/G | |
| Eldest | Adult | 29y | 85y | Adult | Adult | 70s | 8y | Adult | 25y | Adult | 10y | |
| Peripheral NS dysfunction | Kallmann | no | no | no | no | no | 51–75% | yes | 76–100% | 76–100% | no | no |
| CN II: ONH | no | no | no | no | no | no | no | 1–25% | 26–50% | no | no | |
| CN III: CFEOM | 50% | 100% | 76–100% | 100% | 51–75% | 100% | yes | 100% | 100% | 76–100% | 26–50% | |
| CN VII: FW | no | no | no | 51–75% | no | 76–100% | yes | 100% | 100% | no | no | |
| CN IX-XII: Sw. | no | no | no | no | no | no | no | no | 51–75% | no | no | |
| CN X: VC | no | no | no | no | no | no | no | 76–100% | 51–75% | no | no | |
| PN | no | no | no | no | IP 12-45y | teens-60’s | NA | ~20 y | 1-10y | no | no | |
| C contractures | no | no | no | no | no | 51–75% | no | no | 76–100% | no | no | |
| Cyclic vomiting | no | no | no | no | no | no | no | 26–50% | 1–25% | no | no | |
| Cardiac arrhy | no | no | no | no | no | 26–50% | no | 1–25% | 1–25% | no | no | |
| Central NS dysfunction | Microcephaly | no | no | no | no | no | no | no | 1–25% | 26–50% | no | 1–25% |
| Strabismus | S NA | S NA | S NA | S NA | S NA | S NA | S NA | S NA | S NA | S NA | S NA | |
| Nystagmus | N NA | N NA | 1–25% | N NA | 1–25% | N NA | yes | 1–25% | N NA | N NA | N NA | |
| OMA | nr | nr | nr | nr | nr | nr | nr | nr | nr | nr | nr | |
| Seizures | no | no | no | no | no | no | no | 1–25% | 1–25% | no | no | |
| Motor delay | no | no | no | no | no | 26–50% | yes | 76–100% | 76–100% | no | 1–25% | |
| LD | no | no | no | 76–100% | 1–25% | LD NA | no | LD NA | LD NA | 26–50% | LD NA | |
| ID/Social | no | no | no | no | no | 1–25% | yes | 76–100% | 76–100% | no | 76–100% | |
| Brain MRI abnormality | Cerebral cortex | no | no | no | 26–50% | no | no | no | 1–25% | 1–25% | no | 26–50% |
| AC | no | nr | 76–100% | 1–25% | 76–100% | 26–50% | yes | 76–100% | 76–100% | 76–100% | 21–50% | |
| CC | no | no | 1–25% | no | 1–25% | 51–75% | yes | 76–100% | 76–100% | 76–100% | 76–100% | |
| White matter | no | no | no | no | no | 51–75% | no | 76–100% | 76–100% | no | no | |
| Basal ganglia | no | no | mild | no | 1–25% | no | no | no | 76–100% | no | 76–100% | |
| Cerebellum | no | no | no | no | 1–25% | no | no | no | 76–100% | no | 51–75% | |
| Brainstem | no | no | no | no | no | no | no | 1–25% | 76–100% | no | 26–50% |
1Corresponding references reporting each variant are provided in the main text. 2Present in GnomAD with AF of 3.99e-6. 3Pedigree with monozygotic twins. no, absent; nr, not reported or mentioned in publication(s); percentages, percentage range of affected individuals for whom the phenotype has been reported. # Pedigrees, number of pedigrees reported in the literature; # M/F/U/fetus, number of affected individuals who are male, female, unknown or were a fetal case. AD, autosomal dominant; DN, de novo; G, germline mosaic. Eldest, eldest reported individual to date harboring the variant. Y, years of age. Kallmann, anosmia and hypogonadotropic hypogonadism and/or hypoplasia/absence of olfactory sulci and bulbs. CN II: ONH, optic nerve: optic nerve hypoplasia. CN III: CFEOM, oculomotor nerve: congenital fibrosis of the extraocular muscles. CN VII: FW, facial nerve: congenital facial weakness. CN IX-XII: Sw., lower cranial nerves: swallowing dysfunction. CN X: VC, vagal nerve: vocal cord paralysis. PN, mixed sensorimotor axonal polyneuropathy. C contractures, congenital contractures. Cardiac Arrhy, sick sinus syndrome with or without a pacemaker. S NA, strabismus not relevant given CFEOM. N NA, nystagmus not relevant given CFEOM. OMA, oculomotor apraxia. LD, learning disorder. LD NA, LD not relevant given ID/Social disabilities. ID/Social, intellectual and social disabilities (including ASD). Cerebral cortex, malformation of cortical development. AC, hypoplasia or absence of anterior commissure. CC, hypoplasia or absence of corpus callosum. White matter, paucity of central white matter and/or aberrant fascicles or signal where noted. Basal ganglia, presence of any abnormality ranging from mild asymmetry of caudate to full malformation. Cerebellum, malformation of vermis and/or hemispheres. Brainstem, hypoplasia or malformation.