Evaluating the Role of MAST1 as an Intellectual Disability Disease Gene: Identification of a Novel De Novo Variant in a Patient with Developmental Disabilities
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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.
KeywordsMAST1 Whole-exome sequencing Intellectual disability Novel candidate gene Subcellular localization
microtubule associated serine/threonine kinase type 1
developmental delay/intellectual disability
developmental delay/mental retardation
syntrophin-associated serine/threonine kinase
copy number variants
autism spectrum disorders
Al-Ain Medical Human Research Ethics Committee
comparative genomic hybridization
- low IQ
low intelligence quotient
phosphatase and tensin homolog
dystrophin- and utrophin-associated protein complexes.
Special thanks to the family described in this report for their willingness to participate in this study. We are also indebted to the Genotyping and Sequencing core Facilities for their technical help. We are grateful to Mr. Saeed Tariq, from the confocal facility core at the College of Medicine and Health Sciences for his help with confocal microscopy imaging. We would also like to thank United Arab Emirates University for funding this work (grant numbers 31R184 and 31R126).
Compliance with Ethical Standards
The study was approved by Al-Ain Medical Human Research Ethics Committee (AMHREC) according to the national regulations (approval code ERH-2015-3241 15-115).
The authors declare that they have no competing interests.
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