Expanding the Clinical and Molecular Spectrum of TUBB2B Through Distinct Variants Identified Across Multiple Families.

TUBB2B variants (a beta-tubulin isotype) affecting microtubule formation and stability; variant-specific effects, including at a polyamination site.

Description of five individuals from four families carrying rare TUBB2B variants, a beta-tubulin isotype essential for brain development. Variants include previously reported de novo missense changes (with possible phenotypic expansion, including panhypopituitarism), a de novo missense variant at a polyamination site critical for microtubule stability, and a homozygous variant in two siblings from consanguineous parents. The latter two also carried a homozygous truncating ALKBH8 variant, suggesting a dual molecular diagnosis. These observations expand the spectrum of TUBB2B-related tubulinopathies and illustrate the phenotypic heterogeneity.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Beyond phenotypic expansion, the value lies in illustrating two interpretation pitfalls: variant-specific effects (here a polyamination site) and, above all, the dual TUBB2B + ALKBH8 diagnosis, a reminder that finding a plausible variant does not rule out a second cause. It argues for a nuanced genotype-phenotype reading, all the more relevant in exome/genome analysis where multiple diagnoses emerge. The rare recessive form warrants confirmation.

Analysis by Dr Thibaut Benquey