Clinical variability of TUBB-associated disorders: Diagnosis through reanalysis

A range of clinical findings have been associated with heterozygous mutations in the Beta Tubulin (TUBB) gene, including microcephaly, structural brain abnormalities, intellectual disability, and skin creases. We report a 5-year-old male who presented for evaluation of cleft palate, cardiac defects, growth retardation, hemivertebrae causing scoliosis, and preauricular skin tags. Previous clinical exome sequencing of this patient was nondiagnostic, but reanalysis in the research setting identified a de novo missense c. 925C>G p.(Arg309Gly) mutation in TUBB. This mutation was not found in population allele frequency databases, and was classified to be likely pathogenic. This patient shares some phenotypic characteristics with previous reported patients of TUBB mutations of the two TUBB-related phenotypes: "Cortical dysplasia, complex, with other brain malformations 6" [MIM 615771] and "Circumferential Skin Creases Kunze type (CSC-KT)" [MIM 156610], but has no excess skin creases or structural brain anomalies. We also report previously undescribed features, including transposition of the great arteries and vertebral fusion, thus representing phenotype expansion of TUBB-associated disorders.