Expanding the clinical and molecular spectrum of TUBB2B through distinct variants identified across multiple families

Abstract

Summary TUBB2B encodes a β-tubulin isotype essential for neuronal proliferation, migration, and organization during brain development. Pathogenic heterozygous variants in TUBB2B are associated with neurodevelopmental disorders including polymicrogyria and corpus callosum abnormalities. However, the phenotypic spectrum remains heterogeneous, most likely reflecting variant-specific effects on microtubule formation and stability. Homozygous TUBB2B variants are exceedingly rare, with one family reported to date. We describe five individuals in four families with rare TUBB2B variants. Four variants are described, including a previously reported de novo missense variant, c.292G>A (GenBank: NM_178012.5) (p.Gly98Arg), with potential phenotypic expansion including panhypopituitarism; a previously reported de novo missense variant, c.605T>C (GenBank: NM_178012.5) (p.Ile202Thr), showing interindividual heterogeneity; a de novo missense variant, c.43C>A (GenBank: NM_178012.5) (p.Gln15Lys) at a polyamination site critical for microtubule stability; and a homozygous missense variant within a region of absence of heterozygosity in two siblings from consanguineous parents, c.145G>A (GenBank: NM_178012.5) (p.Val49Ile). Both individuals also carry a pathogenic homozygous truncating ALKBH8 variant c.1675del (GenBank: NM_138775.3) (p.Arg559Alafs∗56), representing a potential dual molecular diagnosis driving clinical features reflective of contributions from both genes. These reports expand the clinical spectrum of TUBB2B-related tubulinopathies, illustrate phenotypic heterogeneity, and provide insights into disease mechanisms including effects at polyamination sites and rare recessive inheritance, underscoring the need for nuanced genotype-phenotype interpretation in diagnostic and counseling contexts.