Expanding the Clinical and Molecular Spectrum of tubb2B Through Distinct Variants Identified Across Multiple Families

Authors

• Shaghayegh T Beheshti
• Angad Jolly
• Ahmed K Saad
• Haowei Du
• Lauren E Westerfield
• Chloe Munderloh
• Divya Kalra
• Yifan Wu
• Yi Chen
• Marie-Claude Gingras
• Shalini N Jhangiani
• Sarenur Yilmaz
• Maha S Zaki
• Daniel G Calame
• Davut Pehlivan
• Richard A Gibbs
• Richard A Lewis
• James R Lupski
• Jennifer E Posey

Language

English

Publication Date

10-8-2026

Journal

Human Genetics and Genomics Advances

DOI

10.1016/j.xhgg.2026.100654

PMID

42470103

PMCID

PMC13471236

PubMedCentral® Posted Date

7-17-2026

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Humans, Tubulin, Female, Male, Pedigree, Child, Mutation, Missense, Phenotype, Child, Preschool, Adolescent, Adult, Homozygote, Mutation, TUBB2B, tubulinopathy, neuronal migration disorder, corpus callosum agenesis, septo-optic dysplasia, panhypopituitarism, phenotypic heterogeneity, tubulin polyamination, biallelic TUBB2B variants, dual molecular diagnosis

Published Open-Access

yes

Recommended Citation

Beheshti, Shaghayegh T; Jolly, Angad; Saad, Ahmed K; et al., "Expanding the Clinical and Molecular Spectrum of tubb2B Through Distinct Variants Identified Across Multiple Families" (2026). Faculty, Staff and Students Publications. 8571.
https://digitalcommons.library.tmc.edu/baylor_docs/8571