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TRIO-Related Intellectual Disability

, MD, , PhD, , BSc, MBBS, MD, FRCP, and , MD, PhD.

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Estimated reading time: 18 minutes

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 diagnosis 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 1MethodProportion of Probands with a Pathogenic
Variant 2 Detectable by Method
TRIOSequence analysis 37/8 4 or 16/18 5
Gene-targeted deletion/duplication analysis 61/8 7 or 2/18 5
1.
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. 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.
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.

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:

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:

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/ConcernEvaluationComment
GrowthAssessment of growth parameters to identify those w/failure to thrive
ENT / MouthEvaluation for dental crowding &/or failed/delayed tooth eruptionConsider referral to dentist or orthodontist.
Gastroenterology/
Feeding
Assessment for feeding problems, incl difficulty w/sucking/swallowing, GERD, constipationRefer to feeding therapist if feeding problems are identified.
MusculoskeletalClinical evaluation for scoliosis &/or kyphosisRadiographic 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 ASDConsider referral for formal testing, incl Autism Diagnostic Interview & Autism Diagnostic Observation Schedule.
OtherMultidisciplinary developmental evaluation incl motor, speech/language evaluation, general cognitive & vocational skillsRefer to developmental pediatrician and/or developmental psychologist.
Review of medical history for recurrent infectionsIf 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/ConcernTreatmentConsiderations/Other
Dental crowding /
Malocclusion
Standard treatment as recommended by dentist/orthodontist
Poor weight gain / Failure to thriveFeeding therapy; gastrostomy tube placement may be required for persistent feeding issues.Dietary diary & calorie counts may be requested.
GERD and/or constipationStandard treatment(s)
SeizuresStandard treatment(s) as recommended by neurologist
Scoliosis/KyphosisStandard 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

TRIO-related intellectual disability (ID) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • The majority of individuals diagnosed with TRIO-related ID have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is, however, unknown.
  • Some individuals diagnosed with TRIO-related ID have an affected parent. Because TRIO-related ID is likely underdiagnosed, the actual proportion of simplex cases (defined as individuals with no obvious family history) and familial cases (defined as the presence of ≥2 related affected individuals) cannot be determined.
  • Cumulative data on individuals published to date show that the pathogenic variant was inherited from a similarly affected parent in roughly 40% of individuals reported in smaller studies [Ba et al 2016, Pengelly et al 2016]; inclusion of additional individuals from larger ID/ASD cohorts with suspected diagnosis of TRIO-related ID suggests that this proportion may be as low as 20% (although 20% may reflect an ascertainment bias for individuals with a de novo pathogenic variant in the larger studies).
  • Following identification of a TRIO pathogenic variant in the proband, detailed evaluation of the parental medical history, comprehensive clinical examination, and molecular genetic testing should be offered to both parents to determine if one has a previously unidentified TRIO variant.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent (though theoretically possible, no instances of germline mosaicism have been reported to date).
  • The family history of some individuals diagnosed with TRIO-related intellectual disability may appear to be negative as a result of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to sibs of a proband depends on the genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with TRIO-related ID has a 50% chance of inheriting the TRIO pathogenic variant; intrafamilial clinical variability has been observed [Pengelly et al 2016].

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the TRIO pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the TRIO pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    501 3rd Street Northwest
    Suite 200
    Washington DC 20001
    Phone: 202-387-1968
    Fax: 202-387-2193
    Email: sis@aaidd.org
  • Medline Plus
  • National Center on Birth Defects and Developmental Disabilities
    1600 Clifton Road
    MS E-87
    Atlanta GA 30333
    Phone: 800-232-4636 (toll-free); 888-232-6348 (TTY)
    Email: cdcinfo@cdc.gov
  • VOR: Speaking out for people with intellectual and developmental disabilities
    836 South Arlington Heights Road, #351
    Elk Grove Village IL 60007
    Phone: 877-399-4867
    Fax: 847-253-0675
    Email: info@vor.net

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

TRIO-Related Intellectual Disability: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
TRIO5p15​.2Triple functional domain proteinTRIOTRIO

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for TRIO-Related Intellectual Disability (View All in OMIM)

601893TRIPLE FUNCTIONAL DOMAIN; TRIO
617061INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 44, WITH MICROCEPHALY; MRD44

Gene structure. TRIO spans about 366.5 kb and consists of 57 exons encoding 3,097 amino acids (NM_007118.3). For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Loss-of-function variants have been observed in large-scale reference population datasets (e.g., the Exome Aggregation Consortium [ExAC] dataset) [Lek et al 2016]. Among these, few of the truncating variants are located in the last exon, presumably escaping nonsense-mediated decay (NMD). Although these databases have made attempts to exclude individuals with severe pediatric diseases, this may not be the case for less severe phenotypes [Lek et al 2016].

Pathogenic variants. TRIO pathogenic variants reported include:

Given the small number of affected individuals described to date, de novo variants require detailed clinical assessment to determine if clinical features of TRIO-related ID are present.

Table 4.

TRIO Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.649A>Tp.Arg217TerNM_007118​.3
NP_009049​.2
c.3752delAp.Asp1251ValfsTer11
c.4128G>Ap.Trp1376Ter
c.4283G>Ap.Arg1428Gln
c.4381C>Ap.Pro1461Thr
c.3239A>T 1p.Asn1080Ile 1
c.4466delAp.Gln1489ArgfsTer12

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

No other missense variants lying within the spectrin repeat domain have been reported to date among the well-characterized individuals with TRIO-related ID; thus, the clinical consequences of this variant have not been determined.

Normal gene product. TRIO encodes the triple functional domain protein consisting of several domains, notably an N-terminal SEC14 domain, several spectrin repeats, two Dbl-homology-Pleckstrin-homology (DH-PH) Rho-guanine exchange factor (GEF) domains, and a C-terminal serine/threonine kinase domain. The first DH-PH domain activates Rac1 and RhoG, while the second acts on RhoA. The protein product of TRIO, through its two GEF domains, acts as a Rho GTPase regulator.

Abnormal gene product. Aberrant Rho signaling at the synapse and pathogenic variants in genes encoding the Rho GTPase regulators and effectors have been implicated in human neurologic diseases and intellectual disability [Govek et al 2005, Ba et al 2013]. TRIO is highly expressed at early stages of mammalian development and its expression decreases rapidly during postnatal development, thus suggesting a role in early neuronal development. It has been proposed that TRIO serves as an endogenous break for synaptic development and loss of its activity may induce premature maturation of the excitatory synapses, similar to what has been described in ASD models, through redistribution of postsynaptic AMPA receptors. For a summary refer to Ba et al [2016].

All but one missense or loss-of-function variant associated with disease appeared to affect Trio-mediated Rac1 activation at the functional level [Pengelly et al 2016]. Of note, these variants lie within the first DH-PH GEF domain of the protein. A single variant, however, was predicted to alter a residue within a spectrin repeat (p.Asn1080Ile) and was found not to affect Rac1 activation. Based on this finding and the atypical phenotype of the respective individual, the authors speculated that some features of TRIO-related ID, such as microcephaly or mild speech delay, may be secondary (and specific) to diminished Rac1 activation.

References

Literature Cited

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Chapter Notes

Revision History

  • 10 August 2017 (bp) Review posted live
  • 23 December 2016 (kv) Original submission
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