Trio-Related Intellectual Disability
Summary
Clinical characteristics.
TRIO-related intellectual disability (ID) is characterized by delay in acquisition of motor and language skills, mild to borderline intellectual disability, and neurobehavioral problems (including autistic traits or autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or aggression). Neonatal or infantile feeding difficulties including poor suck, impaired bottle feeding, and failure to thrive are common and are often the presenting finding. Other findings can include microcephaly, variable hand and dental abnormalities, and suggestive facial features. Only ten of the 20 individuals with a TRIO pathogenic variant reported to date had sufficient information to make preliminary generalizations about clinical manifestations; it is anticipated that the phenotype of this newly described disorder will continue to evolve.
Diagnosis/testing.
The diagnosis of TRIO-related ID is established in a proband by identification of a heterozygous TRIO pathogenic variant on molecular genetic testing.
Management.
Treatment of manifestations: Treatment is symptomatic and includes routine management of developmental delays / ID, social and behavior problems, feeding difficulty, and dental abnormalities.
Surveillance: Regular dietary evaluation in infancy to ensure optimal nutritional status; monitoring of developmental progress and educational needs; behavioral assessment for attention, aggression, and/or social communication difficulties; regular dental evaluations.
Genetic counseling.
TRIO-related ID is inherited in an autosomal dominant manner. The majority of affected individuals have the disorder as the result of a de novo pathogenic variant; between 20% and 40% have inherited the TRIO pathogenic variant from a similarly affected parent. Each child of an individual with TRIO-related ID has a 50% chance of inheriting the TRIO pathogenic variant. Once the TRIO pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Diagnosis
No formal clinical diagnostic criteria for TRIO-related intellectual disability (ID) exist.
Suggestive Findings
TRIO-related ID should be considered in individuals with the following clinical findings:
- Delayed speech and fine/gross motor development AND/OR mild (IQ 50-70) to borderline (IQ 70-85) ID; AND
- One or more of the following:
- Microcephaly; occipital-frontal circumference <2 SD
- Minor hand anomalies including short tapering fingers / brachydactyly, broad proximal interphalangeal joints, and clinodactyly of the fifth finger
- Dental anomalies including dental crowding and delayed or failed tooth eruption
- Facial features including facial asymmetry and/or micrognathia
Other, less specific features:
- Neonatal feeding problems that may persist into infancy
- Behavioral problems including autistic traits or autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and/or aggression
- Spinal deformities including scoliosis and/or kyphosis
Establishing the Diagnosis
The diagnosis of TRIO-related ID is established in a proband by identification of a heterozygous pathogenic variant in TRIO on molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of genomic testing (comprehensive genome sequencing) and gene-targeted testing (multigene panel or single-gene testing).
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing does not. As phenotypes of inherited intellectual disability often overlap, most individuals with TRIO-related ID are diagnosed by the following recommended testing or testing to consider.
Recommended Testing
A multigene panel that includes TRIO and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Of note, given the rarity of TRIO-related ID, many panels for intellectual disability may not include this gene.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Testing to Consider
Comprehensive genome sequencing (when clinically available) including exome sequencing and genome sequencing. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Note: Single-gene testing (sequence analysis of TRIO, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.
Table 1.
Molecular Genetic Testing Used in TRIO-Related Intellectual Disability
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| TRIO | Sequence analysis 3 | 7/8 4 or 16/18 5 |
| Gene-targeted deletion/duplication analysis 6 | 1/8 7 or 2/18 5 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Ba et al [2016], Pengelly et al [2016]
- 5.
Proportions when including additional individuals in cohorts with ID or ASD found to have a de novo TRIO variant (presumed to be pathogenic due to their de novo occurrence and the relevant − though not sufficiently evaluated − clinical phenotype) [de Ligt et al 2012, O'Roak et al 2012, Sanders et al 2012, Allen et al 2013, De Rubeis et al 2014, Iossifov et al 2014, Fitzgerald et al 2015]. An additional individual with a de novo intragenic TRIO deletion was reported by the Deciphering Developmental Disorders Study [Fitzgerald et al 2015]. Note that individual #1 from Pengelly et al [2016] was also part of the Deciphering Developmental Disorders Study [Fitzgerald et al 2015].
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
Ba et al [2016]
Clinical Characteristics
Clinical Description
To date, TRIO-related intellectual disability (ID) has been diagnosed in 20 individuals with a de novo TRIO variant identified in several cohorts with ID or autism spectrum disorder (ASD) [de Ligt et al 2012, O'Roak et al 2012, Sanders et al 2012, Allen et al 2013, De Rubeis et al 2014, Iossifov et al 2014, Fitzgerald et al 2015, Ba et al 2016, Pengelly et al 2016]. While the occurrence of a TRIO de novo variant in an individual with ID/ASD would suggest pathogenicity, it is important to consider that because the phenotypic description of TRIO-related ID is incomplete to date, de novo occurrence alone is not sufficient to conclude that a variant is pathogenic [Richards et al 2015].
In ten of these 20 individuals (including the oldest, age 36 years) clinical information was sufficient to make preliminary generalizations about the phenotype. Characteristic findings are developmental delay, mild to borderline ID, and neurobehavioral problems as well as microcephaly, variable hand and dental abnormalities, and suggestive facial features. Nonetheless, a subset of these ten individuals for whom detailed phenotypic information is available do not have obvious clinical findings; thus, TRIO-related ID cannot consistently be identified (or even suspected) by clinical findings alone.
Developmental delay and intellectual disability. All ten individuals had delay in attainment of both motor and speech milestones.
Nine of the ten individuals are verbal; in the most severely affected individuals, first words emerged between ages three and five years. The one nonverbal child relied on alternative forms of communication at age nine years.
Four of the ten individuals had motor delay: sitting unsupported between age nine and 11 months, and walking unaided between age 17 months and four to five years [Pengelly et al 2016].
Eight of the ten clinically well-characterized individuals have mild ID; the other two appear to be functioning at the borderline/normal range of intellectual ability. Individuals in the latter group have experienced delays in language attainment as well as learning difficulties necessitating a specialized school environment. Of note, some individuals have been ascertained only following investigation of a more severely affected family member.
A few older individuals with TRIO-related ID had significant/severe speech delay including the following:
- Individual 1 [Ba et al 2016]. Able to speak five or six words at age seven years
- Individual 5 [Pengelly et al 2016]. First words spoken at age four or five years
- Individual 6 [Pengelly et al 2016]. Nonverbal at age nine years
Behavioral phenotype. Behavioral problems reported in seven of ten of the individuals for whom sufficient clinical information exists include ASD, ADHD, stereotypies, obsessive-compulsive behavior, aggressiveness, self-mutilation, and disrupted sleep.
Of note, no information on the specific behavioral phenotype is available for the individuals with TRIO-related ID who were reported in the context of large ASD cohorts [O'Roak et al 2012, De Rubeis et al 2014, Iossifov et al 2014].
Head size as determined by occipital-frontal circumference (OFC). Microcephaly (<-2 SD) has been observed in seven of ten individuals, five of whom had an OFC 5 SD below the age-appropriate mean, indicating that significant microcephaly may be part of the phenotype.
A few affected individuals have had head measurements within the normal range [Ba et al 2016] or even in the high percentiles [Pengelly et al 2016]. While data are lacking regarding the onset of microcephaly, postnatal onset was reported in one individual [Fitzgerald et al 2015].
Minor hand anomalies. Short tapering fingers with broad proximal interphalangeal joints have been noted in the majority of affected individuals. Other, rarer features may include fifth-finger clinodactyly or appearance of a short palm.
Dental anomalies are dental crowding (4/10 individuals) and delayed or failed tooth eruption (2 additional individuals).
Facial gestalt. There appears to be no recognizable facial gestalt. A significant subset of affected individuals show facial asymmetry (5/10) as well as micrognathia (5/10). Other features include a high forehead (3/10) and synophrys (3/10).
Neonatal or infantile feeding difficulties including poor suck, impaired bottle feeding, and failure to thrive are common and are often the presenting findings, similar to what can be observed in other causes of developmental delay and/or ID. Gastrostomy tube feeding has been required in at least one child.
Spine abnormalities (5/10) are mainly mild scoliosis (3/10) and kyphosis (2/10).
The following features have been observed in fewer individuals:
- Syndactyly of the second and third toes (3/10)
- Recurrent infections (3/10)
- Constipation (2/10)
- Urinary incontinence (2/10)
Other anomalies, each reported in one individual, include:
- Congenital ptosis
- Amblyopia and strabismus
- Hypercalcemia
- Epilepsy
- Tremor
- Wide-based ataxic gait
- Pectus excavatum
Individuals with a de novo presumably pathogenic TRIO variant ascertained from large ID/ASD cohorts. A few of these 11 less well-characterized individuals may have a more severe or complex phenotype as a result of other concomitant genetic findings including single-nucleotide variants or copy-number variants elsewhere in their genome [de Ligt et al 2012, Allen et al 2013, Pengelly et al 2016].
Genotype-Phenotype Correlations
To date the number of published cases (i.e., 10) with detailed genotypic and phenotypic information is insufficient to identify a genotype-phenotype correlation based on the type of TRIO pathogenic variant or the domain of the protein affected.
Penetrance
Information available is insufficient to allow conclusions regarding the penetrance of TRIO pathogenic variants. Based on the family reported by Pengelly et al [2016], some degree of intrafamilial clinical variability can be seen. Variable expressivity may lead to underascertainment of mildly affected individuals and possibly explain the presence (on rare occasions) of individuals harboring presumably pathogenic variants in TRIO in control population-based cohorts such as the Exome Aggregation Consortium (ExAC) [Lek et al 2016].
Prevalence
In the following three studies, TRIO-related ID accounted for seven individuals with ID and/or ASD:
- Three of more than 2,300 individuals with ID had a pathogenic loss-of-function TRIO variant identified by targeted sequencing [Ba et al 2016].
- Three of 1,133 children with severe, undiagnosed developmental disorders had a de novo TRIO pathogenic variant [Fitzgerald et al 2015].
- One of 209 children with ASD who were simplex cases (i.e., a single occurrence in the family) and in whom initial investigation had excluded the presence of large de novo copy number variants had a de novo TRIO pathogenic variant [O'Roak et al 2012].
The prevalence of TRIO-related ID may, however, be difficult to establish given the underascertainment of less severely affected individuals, the ascertainment bias for individuals heterozygous for a de novo or loss-of-function variant, and the genetic testing used to exclude individuals with a known diagnosis from the ID/ASD cohorts studied for TRIO variants.
Differential Diagnosis
Developmental delay, intellectual disability (ID), and/or autism spectrum disorder (ASD) and microcephaly are among the major features in TRIO-related ID for which affected individuals may be referred for genetic evaluation. Phenotypic features associated with TRIO pathogenic variants are not sufficient to diagnose TRIO-related ID.
All genes known to be associated with nonsyndromic intellectual disability (~150 genes have been identified, see OMIM Phenotypic Series: Intellectual disability, autosomal dominant; Intellectual disability, autosomal recessive; and Intellectual disability, nonsyndromic, X-linked) should be included in the differential diagnosis of TRIO-related ID.
Diagnoses that could, however, be considered in individuals with findings suggestive of TRIO-related ID:
- Angelman syndrome (AS), caused by disruption of maternally imprinted UBE3A. Developmental delay and microcephaly are common in AS. One individual with TRIO-related ID had significant motor and language delays and was nonverbal at age nine years; in addition, he had gait anomalies, nocturnal seizures, and facial features reminiscent of AS [Pengelly et al 2016]. However, in TRIO-related ID the degree of developmental delay and ID is usually milder than in AS and seizures are not common, having been reported in only two individuals to date [Allen et al 2013, Pengelly et al 2016].
- MECP2-related disorders, inherited in an X-linked manner. Overlapping features between TRIO-related ID and MECP2-related disorders include developmental delay, microcephaly, and behavioral abnormalities including autistic traits and/or stereotypic behavior and feeding difficulties. The degree of delay is, however, usually less severe in TRIO-related ID, and developmental regression, which is observed in classic Rett syndrome, has not been described to date.
- Pitt-Hopkins syndrome (PTHS), caused by haploinsufficiency of TCF4. Overlapping features include developmental delay and microcephaly. Seizures (although rare in TRIO-related ID) may be part of both disorders. One reported individual with severe ID harbored presumably pathogenic de novo variants in both TCF4 and TRIO, and although his phenotype was considered more compatible with PTHS, the authors debated the phenotypic contribution of the TRIO variants [de Ligt et al 2012]. Episodic hyperventilation has not been described to date in individuals with TRIO-related ID.
Management
Evaluations and Referrals Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with TRIO-related intellectual disability (ID), the evaluations and referrals summarized in Table 2 are recommended.
Note: Some evaluations are age dependent and may not be relevant at the time of initial diagnosis (e.g., recommendation for traits suggestive of an autism spectrum disorder in an infant).
Table 2.
Recommended Evaluations Following Initial Diagnosis of TRIO-Related Intellectual Disability
| System/Concern | Evaluation | Comment |
|---|---|---|
| Growth | Assessment of growth parameters to identify those w/failure to thrive | |
| ENT / Mouth | Evaluation for dental crowding &/or failed/delayed tooth eruption | Consider referral to dentist or orthodontist. |
| Gastroenterology/ Feeding | Assessment for feeding problems, incl difficulty w/sucking/swallowing, GERD, constipation | Refer to feeding therapist if feeding problems are identified. |
| Musculoskeletal | Clinical evaluation for scoliosis &/or kyphosis | Radiographic scoliosis survey (x-rays of spine) based on clinical suspicion; consider referral to orthopedic surgeon if scoliosis is present. |
| Psychiatric/ Behavioral | In individuals age >12 mos: clinical screening for attention/ concentration problems, aggression, &/or traits suggestive of an ASD | Consider referral for formal testing, incl Autism Diagnostic Interview & Autism Diagnostic Observation Schedule. |
| Other | Multidisciplinary developmental evaluation incl motor, speech/language evaluation, general cognitive & vocational skills | Refer to developmental pediatrician and/or developmental psychologist. |
| Review of medical history for recurrent infections | If present, consider referral to immunologist. | |
| Consultation w/clinical geneticist &/or genetic counselor |
ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease
Treatment of Manifestations
See Table 3.
Table 3.
Treatment of Manifestations in Individuals with TRIO-Related Intellectual Disability
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Dental crowding / Malocclusion | Standard treatment as recommended by dentist/orthodontist | |
| Poor weight gain / Failure to thrive | Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues. | Dietary diary & calorie counts may be requested. |
| GERD and/or constipation | Standard treatment(s) | |
| Seizures | Standard treatment(s) as recommended by neurologist | |
| Scoliosis/Kyphosis | Standard treatment as recommended by orthopedist |
GERD = gastroesophageal reflux disease
Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a nationwide federally funded program available in all states.
Ages 3-5 years. In the US, developmental preschool through the local public school district may be considered. An evaluation will occur before placement to determine needed services and therapies and will be subsequently written into an individualized education plan (IEP).
Ages 5-21 years
- In the US, an IEP based on the individual's level of function can be developed by the local public school district. Severely affected children are permitted to remain in the public school district until age 21.
- Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
All ages. Consultation with a developmental pediatrician is recommended to ensure that appropriate community, state, and educational agencies are involved and to support parents.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
- Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Motor Dysfunction
Gross motor dysfunction
- Physical therapy is recommended to maximize mobility.
- Consider use of durable medical equipment as needed (e.g., orthotics, adaptive strollers).
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Oral motor dysfunction. Feeding therapy, typically from an occupational or speech therapist, is recommended for affected individuals who have difficulty feeding due to poor oral motor control, assuming the individual is safe to eat by mouth.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication) for individuals who have expressive language difficulties.
Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Effectiveness should be evaluated on an individual basis.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications (e.g., to treat attention-deficit/hyperactivity disorder) when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Surveillance
The following are appropriate:
- Regular dietary evaluation in infancy to ensure optimal nutritional status
- Monitoring of developmental progress and educational needs
- Behavioral assessment for attention, aggression, and/or social communication difficulties
- Monitoring for spine deformities beginning in early childhood
- Regular evaluation of teeth; frequency determined by a dentist based on dental condition
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.