BRAIN MALFORMATIONS TUBULINOPATHIES PANEL

Scientific Background

Tubulinopathies represent a broad, overlapping spectrum of congenital brain malformations caused by pathogenic variants in one of 8 genes that code for the different isotypes of tubulin. Brain malformations in the context of tubulinopathies can manifest themselves, among other things, in the form of lissencephaly, as classical lissencephaly, lissencephaly with cerebellar hypoplasia, lissencephaly with agenesia of corpus callosum or lissencephaly with pachygyria. Other common malformations are polymicrogyria-like cortical dysplasia, rarefied gyration and microlissencephaly, often in combination with dysplastic basal ganglia, corpus callosum abnormalities as well as hypoplasia or dysplasia of the brain stem and cerebellum.

Clinical symptoms include a global developmental disorder, epilepsy, often primary microcephaly and eye involvement of various degrees. The diagnosis is usually made on the basis of the specific brain malformation findings. Molecular genetic confirmation of the suspected diagnosis can be made by examining the eight known genes that code for the different isotypes of tubulin. Most tubulinopathies follow an autosomal dominant inheritance pattern and are usually caused by spontaneously occurring (de novo) variants in one of the following 6 genes: TUBA1A, TUBB2A, TUBB2B, TUBB3, TUBB and TUBG1. Rarely, homozygous or compound-heterozygous variants in the TUBA8 and TBCD genes can be identified that follow autosomal recessive inheritance.

References

Goncalves et al. 2018, Top Magn Reson Imaging 27:395 / Breuss et al. 2017, Mol Cell Neurosci 84: 58 / Bahi-Buisson et al. 2016, GeneReview 1993 / Mirzaa et al. 2014, Am J Med Genet C Semin Med Genet 166C(2):117 / Fallet-Bianco et al. 2014, Acta Neuropathol Commun 25(2):69