Evaluating the Role of MAST1 as an Intellectual Disability Disease Gene: Identification of a Novel De Novo Variant in a Patient with Developmental Disabilities

Intellectual disability (ID) is one of the most common developmental disorders characterized by a congenital limitation in intellectual functioning and adaptive behavior. More than 800 genes have been implicated so far in the pathogenesis of syndromic and non-syndromic ID conditions with the actual number is expected to be over two thousand. The advent of next-generation sequencing resulted in the identification of many novel ID genes with new genes are being reported on weekly basis. The level of evidence on ID genes varies with some of them being preliminary. MAST1 have been hinted at as being causative of ID but the evidence has been very sketchy. Extensive search of the literature identified three heterozygous de novo missense variants in MAST1 as possible causes of syndromic ID in three individuals where intellectual disability has been a major feature. Using exome sequencing, we identified a novel missense variant c.3539T>G, p.(Leu1180Arg) in MAST1 in an Emirati patient with intellectual disability, microcephaly, and dysmorphic features. In silico pathogenicity prediction analyses predict that all the four missense variants reported in this study are likely to be damaging. Immunostaining of cells expressing human MAST1 showed that majority large proportion of the expressed protein is colocalized the microtubule filaments in the cytoplasm. However, the identified variant c.3539T>G, p.(Leu1180Arg) as well as the other three variants seem to localize in a similar pattern to wild-type indicating a disease mechanism not involving mis-targeting. We, therefore, suggest that mutations in MAST1 should be considered as strong candidates for intellectual disability in humans.