Abstracts

Rationale: To investigate the cause of developmental and epileptic encephalopathy (DEE) in previously undiagnosed patients. Methods: Patients with de novo heterozygous changes in MAST3, a serine-threonine kinase (ST kinase), were identified either through personal communication with researchers and GeneDx or GeneMatcher. These individuals had genetic investigations, through targeted resequencing using single-molecule molecular inversion probes, exome sequencing or genome sequencing. Variant allele frequencies were assessed using gnomAD and TOPMed/Bravo datasets with all variants classified according to the American College of Medical Genetics and Genomics. Patient histories and investigations (genetic, EEGs, MRIs) were collected and reviewed. Results: Seven individuals (2 female; median age 9 years) were identified with missense variants in the MAST3 gene, two of which were recurrent, and all were located in the ST kinase domain. The variants had not been reported in gnomAD, ClinVar or TOPMed databases, and all were predicted to be deleterious by CADD/damaging by PolyPhen. All individuals had DEE with seizure onset before two years (median 11 months) and in 6/7 individuals, seizure onset was associated with regression (language > motor). Prior to seizure onset, 5/7 individuals were developmentally normal. Seizures evolved to include a variety of semiologies, of which generalized tonic-clonic (n=7) and tonic seizures (n=4) were the most common. Current epilepsy control was as follows: intractable (n = 4), moderate (n = 1), seizure free but developmentally delayed (n = 1) and unknown (n = 1). All patients were taking at least one antiepileptic medication (mean=2, range=0 to 3). Six had moderate to severe intellectual disability with global developmental impairment and features of autism. Other common features were hypotonia (n=4), unsteady gait/poor balance (n=5), sleep difficulties (n=5), gastrointestinal difficulties (n=3) and dysmorphic features (n=2). Head circumference was normal in five, large in one and unknown in one. Of the individuals with available MRIs (n=4), all had small pituitaries; brain parenchyma was otherwise unremarkable. Conclusions: We report seven individuals with DEE and common features (early normal development followed by prominent language and motor regression associated with seizure onset and features of autism), who all have de novo variants in MAST3 localized to the protein ST-kinase domain. Functional analysis of these variants is ongoing. MAST3 is the second member of the MAST protein family in addition to MAST1 (mega-corpus callosum syndrome with cerebellar hypoplasia and cortical malformations) to be associated with neurological dysfunction. Funding: No funding