Table 1.
Summary of TUBA1A variants and clinical features.
| Individual 1 | Individual 2 | Individual 3 | |
|---|---|---|---|
| Sex | Female | Male | Female |
| Geographic location/ Ethnicity | USA, Hispanic | USA, Caucasian/Hispanic | French Canadian, Caucasian |
| Variant genomic location (GRCh38/hg38) | chr12:49185150G>C | chr12:49185899C>T | chr12:49185173 A>C |
| Variant (cDNA, protein; transcript NM_006009.4) | c.1216C>G, p.(His406Asp) | c.467G > A, p.(Arg156His) | c.1193T>G, p.(Met398Arg) |
| Exon | 4 | 4 | 4 |
| Inheritance | De novo | De novo | Unknown |
| Method of variant identification | GS | ES | ES |
| Sanger validated? | Y | Y | Y |
| Properties of amino acid residues (WT> Predicted Variant) | Polar basic>Polar acidic | Polar basic>Polar basic | Nonpolar>Polar basic |
| PhyloP score [41, 42]a | 7.76 | 1.91 | 7.32 |
| PHRED-scaled CADD score [43]b | 26.7 | 23.8 | 27.6 |
| ACMG Classification [44]c | Pathogenic | Likely pathogenic | Likely pathogenic |
| Age at clinical presentation | Infancy | Infancy | Infancy |
| Current age | 13 years | 13 years | 11 years |
| Ophthalmological features | |||
| Ophthalmological diagnosis of CFEOM (HP:0001491) | Y | Y | Y |
| Bilateral congenital ptosis (HP:0007911) | Y | Y (right > left) | Y |
| Impaired ocular abduction (HP:0000634) | N | Y, bilateral (mild) | Y, bilateral |
| Impaired ocular adduction (HP:0000542) | N | N | Y, bilateral |
| Limited vertical eye movements | Y, limited upgaze and mildly limited downgaze bilaterally | Y, limited upgaze bilaterally | Y, limited upgaze and downgaze bilaterally |
| Compensatory head posture (HP:0031705) | Y, Chin-up head positioning | Y, Chin-up head positioning | N |
| Abnormal conjugate eye movement (HP:0000549) | Y, convergence on attempted upgaze, divergence and occasional convergence on attempted downgaze | Y, convergence on attempted upgaze with secondary pseudo-convergence contraction nystagmus, left-side synkinetic movement of eyelid | N |
| Anomalous extraocular muscle insertions | Y, of left superior oblique muscle | Y, of right inferior rectus muscle | N |
| Horizontal nystagmus (HP:0000666) | N | N | Y, bilateral |
| Ophthalmological surgeries | Y, bilateral | Y, bilateral | Y, bilateral |
| Development | |||
| Delayed speech and language development (HP:0000750) | Y, mild early delays | N | Y, mild early delays |
| Delayed fine motor development (HP:0010862) | N | Y, mild early delays | Y |
| Delayed gross motor development (HP:0002194) | N | Y, mild early delays | Y |
| Learning disability (HP:0001328) | Y, but no formal diagnosis | N | Y, but no formal diagnosis |
| Cognitive impairment (HP:0100543) | N | N | Delays but no formal diagnosis |
| Attention deficit hyperactivity disorder (HP:0007018) | N | N | Y |
| Oppositional defiant disoder (HP:0010865) | N | N | Y |
| Exam-age | 2 years and 7 months | 2 years and 7 months | 10 years and 10 months |
| Height | 88 cm (18th percentile, z=−0.92) | 90.2 cm (28th percentile; z=−0.57) | 146.3 cm (68.2 percentile, z = 0.44) |
| Weight | 13.8 kg (67th percentile, z = 0.44) | 12.587 kg (24th percentile, z=−0.72) | 31.5 kg (22nd percentile, z=−0.61) |
| Head circumference | 50 cm (89th percentile, z = 1.21) | 48.9 cm (39th percentile, z=−0.28) | 50.7 cm (9th percentile, z=−1.3, Nellhaus Scale) |
| Dysphagia (HP:0002015) | N | None diagnosed, but some choking on solid food | N |
| Ankyloglossia (HP:0010296) | N | Y, relieved with tongue release surgery | N |
| Thickened ears (HP:0009894) | N | N | Y |
| Small forehead (HP:0000350) | N | N | Y |
| Deeply set eyes (HP:0000490) | N | N | Y |
| Infantile muscular hypotonia (HP:0008947) | Y | N | Y |
| Achilles tendon contracture (HP:0001771) | N | N | Y |
| Unsteady gait (HP:0002317) | N | N | Y |
| Tip-toe gait (HP:0030051) | N | N | Y |
| Additional features | |||
| Cyclic/episodic vomiting (HP:0002572) | N | N | Y |
| Gastrointestinal dysmotility (HP:0002579) | N | N | Y |
| Gastroesophageal reflux (HP:0002020) | N | Y | N |
| Brain MRI findings | |||
| Bilateral perisylvian polymicrogyria (HP:0032407) | Y | N | Y |
| Aplasia of the falx cerebri (HP:0010654) | N | Y, slightly interdigitating frontal lobes | N |
| Hypoplasia of the corpus callosum (HP:0002079) | Y | Y | Y |
| Abnormality of the anterior commissure (HP:0030301) | Slightly enlarged | N | N |
| Abnormality of lateral ventricle (HP:0030047) | Y, asymmetry | Y, asymmetry | Y, asymmetry |
| Abnormal caudate nucleus morphology (HP:0002339) | Y, asymmetry of caudate heads | Y, asymmetry of caudate heads | Y, asymmetry of caudate heads |
| Abnormality of brainstem morphology (HP:0002363) | N | Possible slightly obtuse angle between the pons/medulla | N |
| Abnormality of the extraocular muscles (HP:0008049) | Y, superior rectus muscles very small, medial rectus muscles small bilaterally | Y, superior rectus muscles and medial rectus muscles small bilaterally | NA |
Y yes, N no, NA not ascertainable/unknown, ES exome sequencing, GS genome sequencing, CFEOM congenital fibrosis of the extraocular muscles.
aphyloP100way from PHASTv1.5, date of access: November 27, 2020.
bCADDv1.6, date of access: November 27, 2020.
cVariants were classified using ACMG criteria (Richards et al., 2015) in November of 2020. These criteria are not applicable for novel gene identification and have limited utility for significant novel phenotype expansion. Classification is provided for established TUBA1A-associated tubulinopathy phenotypes, but excludes novel phenotype expansions (e.g., CFEOM) which are not yet well established in association with TUBA1A variants.