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

Overview

1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
2. Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, USA
3. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
4. Istanbul Medeniyet University, Istanbul 34000, Turkey
5. Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12622, Egypt
6. Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
7. Texas Children’s Hospital, Houston, TX 77030, USA
8. Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA
9. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
10. Departments of Pediatrics and Medicine, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

• rcsb.org/structure/6e7c, at PDB; found in the text, “Web resources”

Data and code availability

All TUBB2B variants have been submitted to ClinVar (ClinVar: SCV006308805, SCV006308749, and SCV006308014). For subjects who have provided written informed consent for sharing of their genomic data in controlled access databases, these data will be deposited in AnVIL and/or dbGaP under dbGaP: phs000711.v5.p1 and phs003047.v3.p2. Access to these data may be granted to qualified researchers who meet the criteria for access to confidential human subject data, subject to approval by the appropriate IRB and data access committee at BCM.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

• Authors: added Shaghayegh T Beheshti (0000-0002-4092-7703); Jennifer E Posey (0000-0003-4814-6765); removed Shaghayegh T Beheshti; Jennifer E Posey

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 19 authors, 10 keywords, 6 funders, 30 references.

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This paper

Beheshti, S. T., Jolly, A., Saad, A. K., Du, H., Westerfield, L. E., Munderloh, C., Kalra, D., Wu, Y., Chen, Y., Gingras, M.-C., Jhangiani, S. N., Yilmaz, S., Zaki, M. S., Calame, D. G., Pehlivan, D., Gibbs, R. A., Lewis, R. A., Lupski, J. R., & Posey, J. E. (2026). Expanding the clinical and molecular spectrum of TUBB2B through distinct variants identified across multiple families. HGG advances, 7(4), 100654. https://doi.org/10.1016/j.xhgg.2026.100654

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