| Gene | Typical cortical malformation pattern | Key extracortical MRI features | Common clinical features | Epilepsy frequency/notes | Inheritance/recurrence | Key quantitative stats (onset, diagnostic delay, mortality) | Key references |
|---|---|---|---|---|---|---|---|
| **TUBB2A** | Cortical dysplasia, simplified gyral pattern, pachygyria; in the 2021 case series all 3 reported individuals had pachygyria (pqac-00000005) | Dysmorphic corpus callosum; basal ganglia and thalamic abnormalities; brainstem and cerebellar involvement; hypoplastic right caudate nucleus and periaqueductal gray signal abnormality reported in 2 cases (pqac-00000005) | Intellectual disability, hypotonia, developmental delay, seizures; prior reports included infantile spasms (pqac-00000005) | Seizures are recurrently reported, but no robust pooled TUBB2A-specific frequency was available in the gathered evidence (pqac-00000005, pqac-00000003) | Heterozygous pathogenic variants; reports are consistent with predominantly **de novo** occurrence in published cases identified by exome/genome sequencing (pqac-00000005) | No TUBB2A-specific onset, diagnostic-delay, or mortality estimates were available in the gathered evidence (pqac-00000005) | Schmidt et al. 2021, *Molecular Syndromology*, doi:10.1159/000512160, https://doi.org/10.1159/000512160 (pqac-00000005) |
| **TUBB2B** | Predominantly focal perisylvian or generalized polymicrogyria-like cortical dysplasia; diffuse polymicrogyria-like cortical dysplasia also reported; lissencephalic/pachygyric phenotypes can occur but are less common than in TUBA1A (6.8% in the natural-history meta-cohort) (pqac-00000009, pqac-00000011, pqac-00000012) | Basal ganglia involvement/dysmorphism with abnormal or absent anterior limb of the internal capsule; ventriculomegaly; corpus callosum abnormalities/hypoplasia/agenesis; cerebellar hemispheric/vermis abnormalities; small brainstem/pons (pqac-00000001, pqac-00000003, pqac-00000011, pqac-00000012) | Developmental delay/global developmental delay, cognitive and motor impairment, hypotonia or abnormal tone, postnatal microcephaly, ocular abnormalities, severe psychomotor delay/intellectual disability; scoliosis and optic atrophy reported in small series (pqac-00000008, pqac-00000010, pqac-00000011) | Epilepsy in **54.8%** of the 2021 meta-cohort; mean seizure onset **33.1 months** (N=14); **78.6%** of seizures had infantile onset; infantile spasms **27.3%**; refractory epilepsy **37.5%** in available cases. Earlier review reported TUBB2B associated with epilepsy in **74%** of pooled cases and noted often favorable evolution over time (pqac-00000010, pqac-00000003) | Usually **heterozygous de novo** missense variants; recurrence can occur from **maternal germline mosaicism** (same c.728C>T, p.P243L variant in 2 siblings) and low-level mosaic dominant variants are recognized more broadly in polymicrogyria cohorts (pqac-00000001, pqac-00000008, pqac-00000013) | Mean age at disease onset **5.9 ± 8.2 months** (N=17); mean age at genetic diagnosis **12.8 ± 9.5 years**; mean diagnostic delay **12.3 ± 9.9 years**; termination of pregnancy in **7/47 (14.9%)** reported prenatal cases, mean 28 gestational weeks; **93.3%** alive at age **8.0 years** and 2/48 (**4.3%**) deaths during follow-up in the natural-history study (pqac-00000008, pqac-00000009) | Schröter et al. 2021, *Genetics in Medicine*, doi:10.1038/s41436-020-01001-z, https://doi.org/10.1038/s41436-020-01001-z; Romaniello et al. 2019, *Cells*, doi:10.3390/cells8070669, https://doi.org/10.3390/cells8070669; Cushion et al. 2013, *Brain*, doi:10.1093/brain/aws338, https://doi.org/10.1093/brain/aws338; Çitli & Serdaroğlu 2022, *Fetal and Pediatric Pathology*, doi:10.1080/15513815.2020.1753270, https://doi.org/10.1080/15513815.2020.1753270 (pqac-00000008, pqac-00000003, pqac-00000011, pqac-00000013) |
| **Context for real-world diagnosis/testing** | Tubulinopathies are a recognizable MRI-genetics pattern within malformations of cortical development; TUBB2B is a recurring cause in polymicrogyria/deep-sequencing cohorts, while TUBB2A has generally been identified through broad exome/genome testing rather than single-gene testing in the gathered evidence (pqac-00000005, pqac-00000001) | MRI pattern recognition plus genetic testing is standard in published cohorts; deep gene panels improve sensitivity for mosaic variants, whereas exome sequencing has high utility across brain malformations (pqac-00000001, pqac-00000003, pqac-00000009) | Clinical suspicion is driven by developmental delay, epilepsy, and characteristic extracortical anomalies (especially dysmorphic basal ganglia/internal capsule abnormalities) (pqac-00000001, pqac-00000003) | In a 123-patient polymicrogyria deep-sequencing cohort, pathogenic/likely pathogenic variants were found in **25/123 (20.3%)** overall and included **TUBB2B**; in a 102-child brain-malformation exome study, tubulinopathy represented **10%** of phenotypic subtypes and overall clinical singleton exome diagnostic yield was **36%**, rising to **43%** after research follow-up/reanalysis (pqac-00000009, pqac-00000007) | Mosaicism matters for recurrence counseling and detection strategy; parental testing is important when a de novo-appearing variant is found (pqac-00000013, pqac-00000009) | Testing-yield statistics above are not gene-specific for TUBB2A/TUBB2B but reflect current implementation in cortical malformation diagnostics (pqac-00000009, pqac-00000007) | Stutterd et al. 2021, *Brain Communications*, doi:10.1093/braincomms/fcaa221, https://doi.org/10.1093/braincomms/fcaa221; Kooshavar et al. 2024, *Brain Communications*, doi:10.1093/braincomms/fcae056, https://doi.org/10.1093/braincomms/fcae056 (pqac-00000009, pqac-00000007) |


*Table: This table contrasts the cortical malformation, MRI, clinical, inheritance, and quantitative natural-history features supported by the gathered evidence for TUBB2A- and TUBB2B-related tubulinopathies. It also adds a final row summarizing how these genes are currently identified in real-world malformation-of-cortical-development diagnostics.*