Molecular characteristics

The TRIO-related intellectual disability syndrome is molecularly defined by the presence of pathogenic mutations of TRIO on either allele (of paternal or maternal origin) of the affected individuals. Since the exact phenotype is not yet well defined and is – at least at present – rather non-specific, molecular confirmation is necessary for a definitive diagnosis.

To date, more than 10 individuals with pathogenic mutations in TRIO have been identified. In several  cases it is caused by loss-of-function mutations (stopgain or frameshift) in the gene, leading to premature termination and/or degradation of the respective protein product. It is however established that missense mutations or gene deletions can present with similar phenotype, although the pathogenicity of the former is often frequently difficult to establish. Mutations presumed to be pathogenic have on rare occasions been reported in patients belonging to the general – healthy – population perhaps reflecting the mildest (normal) end of the phenotypic spectrum.

TRIO is highly expressed in the developing brain as well as in other tissues though it’s role is not yet well understood. It is believed that the protein product has an important role in neurite development and synaptic transmission. Mutations in TRIO have been shown to markedly reduce Rac1 activation. Although specific domains of the protein have more frequently been implicated in the pathogenesis of the disorder or the presence of specific phenotypes such as the presence or absence of microcephaly, the small number of patients does not allow genotype-phenotype correlation yet.

Several of the individuals have been ascertained following whole exome sequencing, though other techniques such as targeted Sanger sequencing may be helpful in cases where the phenotype is suggestive or in families in which the pathogenic variant has been identified. Even though many patients have the disorder as a result of a de novo pathogenic mutation, a few individuals have also been reported to harbour a pathogenic mutation inherited from a similarly (but more mildy) affected parent.

Prenatal testing may be considered for pregnancies at increased risk, in families in which the pathogenic mutation has been identified.