A Novel Constitutional TUBB Variant Associated With Familial Malformations of Cortical Development.

Constitutional TUBB missense variant [p.(Leu331Phe)] impairing cell motility, cytoskeleton organisation and cell morphology.

Most pathogenic tubulin variants arise de novo in sporadic patients, and the severity of the resulting phenotype usually prevents transmission to offspring. The authors report father-to-daughter transmission of a novel constitutional TUBB variant [NM_178014.4:c.991C>T; p.(Leu331Phe)], both individuals presenting with intellectual disability and a malformation of cortical development. Functional and immunofluorescence assays on patient-derived fibroblasts showed significantly impaired cell motility, altered cytoskeleton organisation and abnormal cell morphology. Combined with a literature review of constitutional and mosaic tubulinopathies, these data indicate that pathogenic germline TUBB variants can occasionally be inherited, transmission being facilitated by a relatively mild anatomoclinical phenotype. The authors recommend comprehensive parental clinical, neuroradiological and genetic evaluation whenever a pathogenic TUBB variant is identified in an index case.

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The message for the clinic is useful: when a tubulinopathy is identified, assuming a de novo event without examining the parents, brain imaging included, risks understating the recurrence risk. The evidence nonetheless rests on a single family with two carriers, and on indirect functional readouts (motility, cytoskeleton) that do not quantify the effect on microtubule dynamics. Further families carrying mildly expressed missense variants would be needed to define penetrance and expressivity.

Analysis by Dr Thibaut Benquey