Biochemistry and Molecular Genetics Department, Hospital Clínic and IDIBAPS, Barcelona, Spain; Centre for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain. Electronic address: [Email]
Microcephaly is a rare condition in which the occipitofrontal circumference in a child is more than two standard deviations below the mean of children of the same age and gender. It is mainly caused by genetic abnormalities that interfere with the growth of the cerebral cortex during early months of fetal development. We present a case of a 12 years old patient with microcephaly. To identify a possible genetic origin of the phenotype, we performed array CGH and exome sequencing in the patient. Exome sequencing revealed the presence of a de novo missense mutation in the TUBB5 gene (E401K). Mutations in the TUBB5 are mainly responsible for microcephaly but the clinical spectrum is wide, from patients with severe developmental delay, and the presence of different brain malformations, to patients with only slightly cognitive impairment and normal motor development. Our patient shows a milder phenotype than other patients carrying the same mutation. These differences in the clinical features suggest that other factors, presumably genetic or epigenetic, could be modulating clinical expressivity of TUBB5. It is therefore evident that more functional studies are needed to understand the pathology that underlies the clinical spectrum of tubulin associated disease states.