Table 1:
Prenatal Imaging Findings, Genetic Testing Results, and Outcomes in Cases of Prenatally Diagnosed Tubulinopathies
| Case | Ultrasound Findings, Gestational Age | MRI Findings, Gestational Age | Test Type | Gene/Inheritance | ACMG Variant Classification | Outcome |
|---|---|---|---|---|---|---|
| 1 | Bilateral ventriculomegaly, absent CSP, dilation of third ventricle – 19 weeks | Absent CSP, cerebellar hypoplasia, supratentorial ventriculomegaly, germinal matrix hemorrhage – 37 weeks | ES | TUBA1A, c.217A>G, heterozygous, unknown inheritance | Likely pathogenic | NSVD at 39 weeks |
| 2 | Absent CSP, cerebellar vermian hypoplasia, prominent frontal horns, underdeveloped third ventricle – 22 weeks | Not performed | Gene panel | TUBA1A, c.190C>T, heterozygous, unknown inheritance | Pathogenic | Pregnancy termination |
| 3 | Bilateral ventriculomegaly, absent CSP, mild cerebellar hypoplasia, prominent third ventricle, microcephaly – 26 weeks | Bilateral ventriculomegaly, cerebellar vermian hypoplasia, microcephaly, thin corpus callosum – 26 weeks | Trio ES | TUBA1A, c.1118G>A, heterozygous, de novo | Likely pathogenic | Pregnancy termination |
| 4 | Bilateral ventriculomegaly, cerebellar vermian hypoplasia – 21 weeks 3 days | Bilateral ventriculomegaly, cerebellar hypoplasia with brainstem kinking, hypotelorism – 24 weeks 3 days | Gene panel | TUBA1A, c.167C>T, heterozygous, unknown inheritance | Pathogenic | CS at 37 weeks |
| 5 | Bilateral ventriculomegaly, wavering midline falx – 20 weeks 4 days | Bilateral ventriculomegaly, cerebellar hypoplasia with abnormal brainstem kinking – 28 weeks 2 days | Gene panel | TUBA1A, c.1216C>T, heterozygous, unknown inheritance | Pathogenic | NSVD at 35 weeks |
| 6 | Cerebellar hypoplasia, micrognathia – 18 weeks | Cerebellar vermian hypoplasia, abnormal appearing gyration, agenesis of the corpus callosum, z- shaped configuration of brainstem – 23 weeks | Trio ES | TUBA1A, c.791G>A, heterozygous, de novo | Likely pathogenic | Pregnancy termination |
| 7 | Flat appearing parieto – occipital and Sylvian fissures – 31 weeks | Cerebellar hypoplasia and bilateral ventriculomegaly – 32 weeks | Trio GS | TUBA1A, c.521C>T, heterozygous, de novo | Likely pathogenic | CS at 41 weeks |
| 8 | Bilateral ventriculomegaly, cerebellar hypoplasia, microcephaly – 20 weeks 5 days | Bilateral ventriculomegaly, cerebellar hypoplasia, microcephaly, interhemispheric cysts – 21 weeks 4 days | Trio ES | TUBA1A, c.47T>C, heterozygous, de novo | Pathogenic | Pregnancy termination |
| 9 | Bilateral ventriculomegaly, absent CSP, agenesis of the corpus callosum – 29 weeks | Cerebellar vermian hypoplasia, dysplasia of the corpus callosum, microcephaly – 30 weeks 3 days | ES | TUBA1A, c.703G>T, heterozygous, unknown inheritance | Likely pathogenic | Pregnancy termination |
| 10 | Bilateral ventriculomegaly, cerebellar hypoplasia – 15 weeks 1 day | Supratentorial ventriculomegaly, cerebellar vermian hypoplasia, hooked appearance of the frontal horns, lissencephaly, pons hypoplasia – 22 weeks | Trio ES | TUBA1A, c.539C>T, heterozygous, de novo | Likely pathogenic | Pregnancy termination |
| 11 | Cystic hygroma −12 weeks | Not performed | Trio ES | TUBA1A, c.687G>C, heterozygous, denovo | Likely pathogenic | Pregnancy termination |
| 12 | Bilateral ventriculomegaly with prominent horns of lateral ventricle, absent CSP – 19 weeks 4 days | Bilateral ventriculomegaly, prominence of lateral ventricles – 19 weeks 5 days | Trio ES | TUBA1A, c.197T>C, heterozygous, de novo | Likely pathogenic | Pregnancy termination |
| 13 | Agenesis of the corpus callosum – 15 weeks 2 days | Agenesis of the corpus callosum, bilateral ventriculomegaly, abnormal frontal and parietal cortical folding, cerebellar vermian hypoplasia with incompletely rotated vermis – 27 weeks 5 days | Trio ES | TUBA1A, c.473C>T, heterozygous, de novo | Likely pathogenic | Pregnancy termination |
| 14 | Dandy walker malformation, enlarged 4th ventricle, bilateral choroid plexus cysts, hypoplastic nasal bone – 20 weeks | Not performed | Trio ES | TUBB, c.185G>A, heterozygous, de novo Multiple regions of homozygosity on array | Likely pathogenic | Pregnancy termination |
| 15 | Mega cisterna magna and cavum vergae – 32 weeks 3 days | Global cerebral loss, ventriculomegaly with markedly diminished white matter, hypoplastic corpus callosum – 32 weeks 4 days | Trio ES | TUBB2A, c.1072C>A, heterozygous, de novo | Likely pathogenic | Pregnancy termination |
| 16 | Bilateral ventriculomegaly, absent CSP, cerebellar hypoplasia – 20 weeks | Supratentorial ventriculomegaly, posterior segment of the corpus callosum not well visualized – 21 weeks | ES | TUBB2B, c.1228G>A, heterozygous, unknown inheritance | Pathogenic | Pregnancy termination |
| 17 | Bilateral ventriculomegaly, cerebellar vermian hypoplasia, arthrogryposis, fixed posturing of upper and lower limbs – 15 weeks | Not performed | Trio ES | TUBB2B, c.1172G>T, heterozygous, de novo | Likely pathogenic | Pregnancy termination |
| 18 | Possible agenesis of the corpus callosum – 29 weeks | Corpus callosum present, bilateral ventriculomegaly, unusually shaped left lateral sulcus – unknown gestational age | ES | TUBB3, c.586G>A, heterozygous, unknown inheritance | Likely pathogenic | Full term with unknown mode of delivery |
| 19 | Bilateral ventriculomegaly – 20 weeks | Bilateral ventriculomegaly, asymmetric sulcation delay, abnormal brainstem transition with a prominent medulla – 24 weeks | Gene panel | Deletion of 293 kb at 6q22.3, maternally inherited TUBB3, c.836A>G, heterozygous, unknown inheritance | Likely benign Likely pathogenic |
NSVD at 38 weeks 5 days |
All probands had a chromosomal microarray, and abnormal variants are detailed above
Abbreviations: ACMG, American College of Medical Genetics; CSP, Cavum septum pellucidum; NSVD, Normal spontaneous vaginal delivery; ES, Exome sequencing; GS, Genome sequencing; CS; Caesarean section