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

TUBB2B encodes a β-tubulin isotype essential for neuronal proliferation, migration, and organization during brain development. Pathogenic heterozygous variants in TUBB2B have been associated with a range of neurodevelopmental disorders, with phenotypes including polymicrogyria and corpus callosum abnormalities. However, the phenotypic spectrum remains heterogeneous, likely influenced by variant-specific effects on microtubule formation and stability, an area that warrants further investigation. Homozygous TUBB2B variants are exceedingly rare, with one family reported to date. We describe five individuals in four families with rare TUBB2B variants. Four variant alleles are described, including a previously reported de novo missense variant p.(G98R), with potential phenotypic expansion including panhypopituitarism, a previously reported de novo missense variant, p.(I202T) demonstrating phenotypic heterogeneity between individuals, a de novo missense variant, p.(Q15K) at a polyamination site critical for microtubule stability, and a novel homozygous missense variant located within a region of absence of heterozygosity in two siblings from consanguineous parents p.(V49I). Both individuals also have a pathogenic homozygous truncating variant in ALKBH8 p.(R559Afs*56), representing a rare dual molecular diagnosis driving clinical features reflective of contributions from both genes. These cases expand the known clinical spectrum of TUBB2B-related tubulinopathies, illustrate intragenic phenotypic heterogeneity, including with recurrent variants and provide novel insights into potential mechanisms of disease, such as effects at polyamination sites and rare recessive inheritance, underscoring the need for nuanced genotype-phenotype interpretation in both diagnostic and counseling contexts.