A Novel Constitutional TUBB Variant Associated With Familial Malformations of Cortical Development.
TL;DR
The father-to-daughter transmission of a novel constitutional TUBB variant, alongside literature review of constitutional and mosaic tubulinopathies, suggest that pathogenic germline TUBB variants can occasionally be inherited.
Abstract
Most pathogenic tubulin variants arise de novo in sporadic patients, causing severe brain malformations and significant neurodevelopmental impairment. The resulting reproductive disadvantage typically prevents these mutations from being transmitted to offspring. While a few variants are inherited from somatic or gonadal mosaic parents, vertical transmission of constitutional variants remains rare, though increasingly documented. Here, we report the father-to-daughter transmission of a novel constitutional TUBB variant [NM_178014.4:c.991C>T; p.(Leu331Phe)]. Both individuals presented with intellectual disability and a malformation of cortical development (MCD). To validate the pathogenicity of this variant, we performed functional and immunofluorescence assays in vitro on patient-derived fibroblast cultures. These experiments supported the involvement of the variant in significantly impairing cell motility, altering cytoskeleton organization, and affecting cellular morphology. Our findings from this family, alongside literature review of constitutional and mosaic tubulinopathies, suggest that pathogenic germline TUBB variants can occasionally be inherited. Transmission is facilitated by the relatively mild clinical anatomoclinical phenotype. When a pathogenic TUBB variant is identified in an index patient, comprehensive parental clinical, neuroradiological, and genetic evaluation is crucial to accurately assess reproductive risk.