Identification of two novel de novo TUBB variants in cases with brain malformations: case reports and literature review

• Published in: Journal of human genetics Vol. 66; no. 12; pp. 1193 - 1197
• Main Authors: Watanabe, Kazuki, Nakashima, Mitsuko, Kumada, Satoko, Mashimo, Hideaki, Enokizono, Mikako, Yamada, Keitaro, Kato, Mitsuhiro, Saitsu, Hirotomo
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01-12-2021
• Subjects: Age; Alleles; Basal ganglia; Birth weight; Brain - abnormalities; Brain stem; Case reports; Cerebellum; Congenital defects; Corpus callosum; Dysplasia; Dystonia; Gait; Genetic Association Studies; Genetic Predisposition to Disease; Genetics; Genotype; Humans; Isotypes; Literature reviews; Magnetic resonance imaging; Medicine; Microcephaly; Mutation; Nervous System Malformations - diagnosis; Nervous System Malformations - genetics; Neurodevelopmental disorders; Phenotype; Skin; Spasticity; Strabismus; Tubulin; Tubulin - genetics; Tubulin - metabolism; Walking
• ISSN: 1434-5161; 1435-232X
• DOI: 10.1038/s10038-021-00956-4

Heterozygous variants in TUBB encoding one of β-tubulin isotypes are known to cause two overlapping developmental brain disorders, complex cortical dysplasia with other brain malformations (CDCBM) and congenital symmetric circumferential skin creases (CSCSC). To date, six cases of CSCSC and eight cases of CDCBM caused by nine heterozygous variants have been reported. Here we report two cases with novel de novo missense TUBB variants (NM_178014.4:c.863A>G, p.(Glu288Gly) and c.869C>T, p.(Thr290Ile)). Case 1 presented brain malformations consistent with tubulinopathies including abnormalities in cortex, basal ganglia, corpus callosum, brain stem, and cerebellum along with other systemic features such as coloboma, facial dysmorphisms, vesicoureteral reflux, hypoplastic kidney, and cutis laxa-like mild skin loosening. Another case presented abnormalities of the corpus callosum, brain stem, and cerebellum along with facial dysmorphisms. We reviewed previous literature and suggest the diversity of clinical findings of TUBB-related disorders.