TUBG1 – Lissencephaly Spectrum Disorders

Gamma-tubulin 1 (TUBG1) is essential for microtubule nucleation at the centrosome and neuronal migration. Heterozygous missense variants in TUBG1 have been increasingly recognized as a cause of malformations of cortical development, most notably lissencephaly and pachygyria spectrum disorders (smooth brain) ([PMID:38912084]).

A 1½-year-old girl presented with global developmental delay, microcephaly, infantile-onset epilepsy with epileptic spasms, ventriculomegaly and pachygyria on MRI. Whole-exome sequencing identified a de novo NM_001070.5:c.530A>G (p.Glu177Gly) variant in TUBG1, concordant with the clinical phenotype, establishing a molecular diagnosis of TUBG1-associated cortical malformation ([PMID:38912084]).

In a retrospective cohort of 811 lissencephaly and subcortical band heterotopia patients, targeted sequencing of 17 genes revealed that TUBG1 variants accounted for approximately 1% of cases. Two unrelated patients harbored NM_001070.5:c.776C>T (p.Ser259Leu) and NM_001070.5:c.769A>T (p.Ile257Phe), consistent with autosomal dominant, de novo inheritance ([PMID:29671837]).

Functional assessment of TUBG1 missense variants (including p.Tyr92Cys and p.Ser259Leu) demonstrated disrupted neuronal locomotion and reduced microtubule dynamics without affecting progenitor proliferation, both in subject-derived fibroblasts and in utero electroporation assays. A knock-in Tubg1Y92C/+ mouse model recapitulated neuroanatomical defects and increased epileptic cortical activity, confirming pathogenicity via a dominant-negative or haploinsufficiency mechanism ([PMID:31086189]).

Across these reports, at least four unrelated probands have de novo TUBG1 missense variants with no reported segregation in multiplex families. The convergence of multiple independent case reports and robust in vivo/in vitro functional data supports a Moderate ClinGen gene–disease association for TUBG1 and lissencephaly spectrum disorders.

Key Take-home: Heterozygous de novo missense variants in TUBG1 cause a clinically recognizable tubulinopathy with lissencephaly, refractory epilepsy and developmental delay, and should be included in diagnostic gene panels.

References

• Cureus • 2024 • Gamma-Tubulin 1 (TUBG1) Mutation-Associated Lissencephaly and Microcephaly in an Indian Child: A Rare Case. PMID:38912084
• Genetics in Medicine • 2018 • Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly. PMID:29671837
• Nature Communications • 2019 • TUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis. PMID:31086189

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