MAST1 mutations

Inspired by a patient

Abstract Number: (223)  ACMG Annual Clinical Genetics Meeting 2018

De novo variants in MAST1 are associated with a novel neurodevelopmental disorder characterized by microcephaly and brain malformations

Topic: Clinical Genetics

First Author: Wei Shen, PhD, University of Utah

Presenting Author: Wei Shen, PhD, University of Utah

Co-Authors: T. Tvrdik, University of Utah; T. Tidwell, ARUP Laboratories; L. Botto, University of Utah; J. Bale, University of Utah; A. Andrews, University of Utah; D. Ball, University of Utah; F. Filloux, University of Utah; C. Van Orman, University of Utah; K. Dent, University of Utah; J. Palumbos, University of Utah; C. Miller, ARUP Laboratories; S. Brown, ARUP Laboratories; P. Krautscheid, ARUP Laboratories; J. Carey, University of Utah; R. Mao, University of Utah; P. Bayrak-Toydemir, ARUP Laboratories/University of Utah School of Medicine

Description:

Human MAST1 encodes microtubule associated serine/threonine kinase 1, which is predominately expressed in the brain. In mouse, MAST1 interacts with syntrophin through the PDZ domain. To date, no human disease association has been established for MAST1. de Ligt (2012) and Gilissen (2014) reported a de novo MAST1 variant, c.3530C>G, p.Pro1177Arg, in an individual with microcephaly, global developmental delay, intellectual disability, partial agenesis of corpus callosum and an arachnoid cyst in the posterior fossa. Several additional de novo missense variants of MAST1 have been reported in the large cohort studies of individuals with developmental disorders, intellectual disability, and cerebral palsy. However, clinical descriptions of these individuals are not available. 

Here we report 3 unrelated patients with overlapping neurological phenotypes and de novo missense variants in MAST1 identified by clinical exome sequencing. Two patients had de novo missense variants that alter the same amino acid Pro1177 as the variant reported by Gilissen (2014) (Patient 1: c.3530C>T, p.Pro1177Leu; Patient 2: c.3529C>T, p.Pro1177Ser). Patient 3 carried a different de novo variant c.3889G>T, p.Asp1297Tyr. All 3 patients had microcephaly, severe global developmental delay, and intellectual disability with absent speech or speech delay. In Patient 1, brain MRI showed hypoplasia of corpus callosum and cerebellar vermis, and periventricular white matter loss. In Patients 2 and 3, brain MRI demonstrated partial agenesis of corpus callosum and pontocerebellar hypoplasia. Patient 2 also exhibited delayed myelination, whereas Patient 3 had an arachnoid cyst over the posterior left frontal lobe. 

We compiled the previously reported MAST1 de novo variants. All 8 variants are missense alterations not observed in the population variant databases. Three missense variants alter the same codon Pro1177. Computational analysis predicted that all 8 MAST1 missense variants would impact protein function. Functional consequences of these MAST1 missense variants are under nvestigation. 

Our results support that MAST1 de novo variants are associated with an emergent autosomal dominant neurodevelopmental disorder characterized by microcephaly, global developmental delay, intellectual disability, and brain malformations.