MAST1-Gene Variations: A New Monogenetic Neuronal Migration Disorder Causing Congenital Bilateral Perisylvian Syndrome (CBPS)

Background: Congenital bilateral perisylvian syndrome (CBPS) is a rare cortical migration disorder associated with typical clinical and imaging features such as bilateral symmetrical polymicrogyria, either exclusively or mainly affecting the perisylvian region of the brain. Clinical features of CBPS often include oromotor dysfunction, epilepsy and variable degrees of developmental delay. There are multiple non-genetic causes of polymicrogyria and CBPS in particular, including vascular and hypoxemic insults or congenital infections. Up to now genetic causes have been rarely reported, mostly associated with syndromic forms or peroxisomal disorders.

Case: We present a girl with complex migration disorder predominantly presenting with bilateral symmetrical polymicrogyria especially around the Sylvian fissure and corpus callosum hyperplasia. At the age of 10-month the girl presented with a global developmental delay, difficult to treat seizures and severe oromotor dysfunction causing recurrent airway infections. There was no evidence for vascular or hypoxemic insults or congenital infection so that a genetic cause was proposed.

Methods: We performed a trio-based whole exome sequencing (WES) with DNA samples isolated from blood lymphocytes of both healthy parents and the index patient.

Results: Using Trio-WES we identified a non-annotated de novo 22 base pair deletion in MAST1 (NM_014975.2), c.669_689del, [p.(Gln223_Asp230delinsHis)]. Sanger sequencing confirmed this variant and its de novo occurrence. It affects a highly conserved region and is predicted to have a deleterious effect on the protein function. At the time of its identification, MAST1 was not associated with disease but using the platform GeneMatcher we got aware of an international collaboration which collected six further cases with de novo MAST1-mutations. Their data have recently been reported as mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCCCHCM).

Discussion: MAST1 is part of the Microtubule-Associated Serine/Threonine Kinase family and has a role in sustaining the synaptic structure and ensuring the signal transmission at the neuromuscular junction. The highest MAST1 expression in developing human brains has been seen in gestation weeks 13 and 22, just when the major neuronal migration occurs which is between the 12th and the 24th weeks of gestation. Cortex development and late migration continues until five months postnatally but especially the perisylvian region is one of the earliest-developing sulci of the human brain. Our patient and the six further patients, shortly reported with MAST1-mutations, all show the leading symptoms of CBPS which are global developmental delay, hypotonia and oromotor dysfunction. In all cases the MRI showed a complex migration disorder with a hyperplastic corpus callosum, ventricular dilation and pontine hypoplasia. In conclusion, MAST1 mutations should be kept in mind as a monogenetic cause for CBPS.