A Case of Complex Cortical Dysplasia with Other Brain Malformations Type 1

doi:10.12280/gjszjk.20250532

Abstract

Abstract:

Complex cortical dysplasia with other brain malformations type 1 (CDCBM1) is a disorder characterized by abnormal neuronal migration and axonal guidance defects, clinically presenting with intellectual disability, strabismus, reduced axial tone, and epilepsy. We report a case of a child presenting with developmental delay, cognitive impairment, and abnormal brain development. Trio-whole exome sequencing revealed a heterozygous missense mutation c.862G>A(p.Glu288Lys) in exon 4 of the TUBB3 gene, validated by Sanger sequencing. Neither parent carried this variant. According to the American College of Medical Genetics and Genomics (ACMG) criteria, this variant is classified as likely pathogenic (PS2+PM2+PP2). The TUBB3 gene encodes β-Ⅲ tubulin. The genetic testing results indicated that this case of CDCBM1 was caused by the heterozygous missense mutation c.862G>A(p.Glu288Lys) in TUBB3 gene, providing the evidence for the clinical diagnosis and genetic counseling of this family.

Key words: Malformations of cortical development, Tubulin, Mutation, Whole exome sequencing, TUBB3 gene

WANG Yu-pei, ZHAI Xi-guo, ZHANG Chuan, LIANG Li, ZHU Jing, HUI Ling. A Case of Complex Cortical Dysplasia with Other Brain Malformations Type 1[J]. Journal of International Reproductive Health/Family Planning, 2026, 45(2): 116-119.

Figures/Tables 3

References 15

[1]	Radwitz J, Hausrat TJ, Heisler FF, et al. Tubb3 expression levels are sensitive to neuronal activity changes and determine microtubule growth and kinesin-mediated transport[J]. Cell Mol Life Sci, 2022, 79(11):575. doi: 10.1007/s00018-022-04607-5. pmid: 36309617
[2]	LaFrance BJ, Roostalu J, Henkin G, et al. Structural transitions in the GTP cap visualized by cryo-electron microscopy of catalytically inactive microtubules[J]. Proc Natl Acad Sci U S A, 2022, 119(2):e2114994119. doi: 10.1073/pnas.2114994119.
[3]	Roll-Mecak A. The Tubulin Code in Microtubule Dynamics and Information Encoding[J]. Dev Cell, 2020, 54(1):7-20. doi: 10.1016/j.devcel.2020.06.008. pmid: 32634400
[4]	Poirier K, Saillour Y, Bahi-Buisson N, et al. Mutations in the neuronal ß-tubulin subunit TUBB3 result in malformation of cortical development and neuronal migration defects[J]. Hum Mol Genet, 2010, 19(22):4462-4473. doi: 10.1093/hmg/ddq377. pmid: 20829227
[5]	Tischfield MA, Baris HN, Wu C, et al. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance[J]. Cell, 2010, 140(1):74-87. doi: 10.1016/j.cell.2009.12.011. pmid: 20074521
[6]	Löwe J, Li H, Downing KH, et al. Refined structure of alpha beta-tubulin at 3.5 A resolution[J]. J Mol Biol, 2001, 313(5):1045-1057. doi: 10.1006/jmbi.2001.5077. pmid: 11700061
[7]	Qu C, Dwyer T, Shao Q, et al. Direct binding of TUBB3 with DCC couples netrin-1 signaling to intracellular microtubule dynamics in axon outgrowth and guidance[J]. J Cell Sci, 2013, 126(Pt 14):3070-3081. doi: 10.1242/jcs.122184. pmid: 23641072
[8]	Zhu K, Wang H, Ye K, et al. Netrin-1 signaling pathway mechanisms in neurodegenerative diseases[J]. Neural Regen Res, 2025, 20(4):960-972. doi: 10.4103/NRR.NRR-D-23-01573. pmid: 38989931
[9]	Huang H, Yang T, Shao Q, et al. Human TUBB3 Mutations Disrupt Netrin Attractive Signaling[J]. Neuroscience, 2018, 374:155-171. doi: 10.1016/j.neuroscience.2018.01.046. pmid: 29382549
[10]	Shao Q, Yang T, Huang H, et al. Uncoupling of UNC5C with Polymerized TUBB3 in Microtubules Mediates Netrin-1 Repulsion[J]. J Neurosci, 2017, 37(23):5620-5633. doi: 10.1523/JNEUROSCI.2617-16.2017.
[11]	Itai T, Jia P, Dai Y, et al. De novo mutations disturb early brain development more frequently than common variants in schizophrenia[J]. Am J Med Genet B Neuropsychiatr Genet, 2023, 192(3/4):62-70. doi: 10.1002/ajmg.b.32932.
[12]	Galatolo D, De Michele G, Silvestri G, et al. NGS in Hereditary Ataxia: When Rare Becomes Frequent[J]. Int J Mol Sci, 2021, 22(16):8490. doi: 10.3390/ijms22168490.
[13]	Halvorsen M, Samuels J, Wang Y, et al. Exome sequencing in obsessive-compulsive disorder reveals a burden of rare damaging coding variants[J]. Nat Neurosci, 2021, 24(8):1071-1076. doi: 10.1038/s41593-021-00876-8. pmid: 34183866
[14]	Froukh TJ. Next Generation Sequencing and Genome-Wide Genotyping Identify the Genetic Causes of Intellectual Disability in Ten Consanguineous Families from Jordan[J]. Tohoku J Exp Med, 2017, 243(4):297-309. doi: 10.1620/tjem.243.297. pmid: 29269699
[15]	Whitman MC, Andrews C, Chan WM, et al. Two unique TUBB3 mutations cause both CFEOM3 and malformations of cortical development[J]. Am J Med Genet A, 2016, 170A(2):297-305. doi: 10.1002/ajmg.a.37362. pmid: 26639658