Clinical Guidance

Gain-of-function missense variants (affecting the spectrin repeat domain) are associated with more severe developmental delay and intellectual disability, macrocephaly, and a higher risk of seizures and scoliosis than individuals with loss-of-function variants. Pathogenic variants involving p.Arg1078 were reported to be associated with the most severe phenotype . Loss-of-function missense variants within the GEFD1 domain as well as truncating variants throughout the gene cause less severe intellectual disability than gain-of-function variants and microcephaly in some individuals.

Source: GeneReviews — "TRIO-Related Neurodevelopmental Disorder"

Penetrance

Penetrance appears to be complete. Based on the seven individuals (from five families) in whom the TRIO pathogenic variant was inherited [; ; ; Gazdagh et al, unpublished data], the parent may be similarly or only mildly affected compared to the index case within a family.

Source: GeneReviews — "TRIO-Related Neurodevelopmental Disorder"

Diagnostic Criteria

Suggestive Findings

TRIO-related neurodevelopmental disorder (TRIO-NDD) should be considered in individuals with any combination of the following clinical findings:

Source: GeneReviews — "TRIO-Related Neurodevelopmental Disorder"

Differential Diagnosis

Developmental delay, intellectual disability, and/or neurobehavioral manifestations and abnormal head circumference are among the major features in TRIO-related neurodevelopmental disorder (TRIO-NDD) for which affected individuals may be referred for genetic evaluation. Because these features are not sufficient to diagnose TRIO-NDD, all intellectual developmental disorders without other distinctive findings should be considered in the differential diagnosis. See OMIM Autosomal Dominant, Autosomal Recessive, Nonsyndromic X-Linked, and Syndromic X-Linked Intellectual Developmental Disorder Phenotypic Series.

Source: GeneReviews — "TRIO-Related Neurodevelopmental Disorder"

Management Guidelines

No clinical practice guidelines for TRIO-related neurodevelopmental disorder (TRIO-NDD) have been published. Evaluations and Referrals Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with TRIO-NDD, the evaluations and referrals summarized (if not performed as part of the evaluation that led to diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis of TRIO-Related Neurodevelopmental Disorder

Source: GeneReviews — "TRIO-Related Neurodevelopmental Disorder"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "TRIO-Related Neurodevelopmental Disorder"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 5. Recommended Surveillance for Individuals with TRIO-Related Neurodevelopmental Disorder

Source: GeneReviews — "TRIO-Related Neurodevelopmental Disorder"