Thoc6 Intellectual Disability Syndrome
Summary
Clinical characteristics.
THOC6 intellectual disability syndrome is associated with moderate-to-severe developmental delay or intellectual disability; nonspecific dysmorphic facial features (tall forehead, deep-set eyes, short and upslanted palpebral fissures, epicanthal folds, and long nose with low-hanging columella); microcephaly (typically 2-3 SD below the mean); teeth anomalies (dental caries, malocclusion, and supernumerary teeth); cardiac anomalies (most typically atrial and/or ventricular septal defects); prenatal ventriculomegaly and hydrocephalus; cryptorchidism in males; and renal malformations (most commonly unilateral renal agenesis). More rarely, affected individuals may have hypergonadotropic hypogonadism (in females), seizures, poor growth, feeding difficulties, hearing loss, refractive errors and/or other eye abnormalities, vertebral anomalies, micro/retrognathia, and imperforate / anteriorly placed anus.
Diagnosis/testing.
The diagnosis of THOC6 intellectual disability syndrome is established in a proband with biallelic pathogenic variants in THOC6 identified by molecular genetic testing. For individuals from the Hutterite population suspected of having THOC6 intellectual disability syndrome, molecular genetic testing for the specific c.136G>A (p.Gly46Arg) founder variant can be considered.
Management.
Treatment of manifestations: For those with poor weight gain, feeding therapy and consideration of a gastrostomy tube; for those with hearing loss, hearing aids may be considered; standard treatment for seizures, vision issues, dental caries/malocclusion, cardiac malformations, genital anomalies, hypergonadotropic hypogonadism, renal malformations, skeletal anomalies, and developmental delay / intellectual disability.
Surveillance: At each visit: monitor developmental progress, mobility, self-help skills, and behavior; assess for signs and symptoms of hydrocephalus or for new neurologic manifestations; measurement of growth parameters and evaluation of nutritional status; assessment of vision and eye alignment; assessment for dental caries and malocclusion. Evaluate renal function (BUN, creatinine, and urinalysis) at each visit or annually for those with anomalies of the kidney and urinary tract; annual audiology evaluation; evaluation of secondary sexual characteristics and menstrual cycles at each visit in females older than age 12 years.
Genetic counseling.
THOC6 intellectual disability syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in an affected family member.
Diagnosis
Formal diagnostic criteria for THOC6 intellectual disability syndrome have not been established.
Suggestive Findings
THOC6 intellectual disability syndrome should be considered in individuals with the following clinical and imaging findings:
- Moderate-to-severe developmental delay (DD) or intellectual disability (ID)AND
- One or more of the following features presenting in infancy or childhood:
- Microcephaly
- Multiple dental caries and/or dental malocclusion
- Nonspecific dysmorphic features, including tall forehead, deep set eyes, short and upslanted palpebral fissures, epicanthal folds and long nose with low hanging columella
- Cryptorchidism in males
- Structural cardiac anomalies
- Structural renal anomalies
- Ventriculomegaly on brain imaging
Establishing the Diagnosis
The diagnosis of THOC6 intellectual disability syndrome is established in a proband with biallelic pathogenic variants in THOC6 identified by molecular genetic testing (see Table 1).
Molecular Genetic Testing
Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability typically begins with chromosomal microarray analysis (CMA). CMA uses oligonucleotide and/or SNP arrays to detect genome-wide large deletions/duplications (including THOC6) that cannot be detected by sequence analysis.
If CMA is not diagnostic, the next step is typically either a multigene panel or exome sequencing.
- For individuals from the Hutterite population suspected of having THOC6 intellectual disability syndrome, molecular genetic testing for the specific c.136G>A (p.Gly46Arg) founder variant can be considered first (see Molecular Genetics).
- For individuals who do not originate from the Hutterite population, single-gene testing (sequence analysis of THOC6, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (CMA, exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of THOC6 intellectual disability syndrome is somewhat nonspecific, the majority of affected individuals have a phenotype indistinguishable from many other inherited disorders with intellectual disability. Therefore, targeted genomic testing (Option 1) or comprehensive genomic testing (Option 2) are the most reasonable methods to detect this condition.
Option 1
An intellectual disability or microcephaly multigene panel that includes THOC6 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA 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. 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. Of note, given the rarity of THOC6 Intellectual disability syndrome, some panels for intellectual disability may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability and other malformations, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in THOC6 Intellectual Disability Syndrome
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| THOC6 | Sequence analysis 3 | 15/15 (100%) 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown 6 |
- 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.
Boycott et al [2010], Beaulieu et al [2013], Anazi et al [2016], Casey et al [2016], Amos et al [2017], Accogli et al [2018], Nair et al [2018], Bruel et al [2019], Elmas et al [2019], Mattioli et al [2019], Gupta et al [2020], Zhang et al [2020]
- 5.
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. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods.
- 6.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Clinical Characteristics
Clinical Description
THOC6 intellectual disability syndrome is associated with intellectual disability, distinctive facial features, microcephaly, teeth anomalies, and cardiac and renal malformations. To date, 19 individuals from 15 families with pathogenic variants in THOC6 have been identified [Boycott et al 2010, Beaulieu et al 2013, Anazi et al 2016, Casey et al 2016, Amos et al 2017, Accogli et al 2018, Nair et al 2018, Bruel et al 2019, Elmas et al 2019, Mattioli et al 2019, Gupta et al 2020, Zhang et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports.
Table 2.
Features of THOC6 Intellectual Disability Syndrome
| Feature | Proportion of Persons w/Feature | Comment |
|---|---|---|
| Intellectual disability | 19/19 | Moderate to severe |
| Facial dysmorphisms | 17/19 | |
| Microcephaly | 13/19 | |
| Teeth anomalies | 10/19 | Dental caries & dental malocclusion |
| Congenital heart defects | 9/19 | Atrial &/or ventricular septal defects |
| Short stature | 8/19 | |
| Cryptorchidism in males | 7/19 | |
| Renal malformations | 6/19 | Mainly unilateral renal agenesis |
| Ventriculomegaly 1 | Observed in at least 6 persons |
- 1.
Ventriculomegaly may not have been assessed in all 19 reported cases in the literature so this may underestimate the actual incidence.
Developmental Delay (DD) / Intellectual Disability (ID)
Moderate-to-severe intellectual disability has been noted in all reported individuals. Most of these individuals were able to walk independently, but remained nonverbal or had very limited speech (<10 words). The oldest reported individuals are young adults.
Behavior problems. Autism spectrum disorder and motor stereotypies were described in four individuals [Accogli et al 2018, Elmas et al 2019, Mattioli et al 2019]. Obsessive compulsive behavior was observed in one individual [Amos et al 2017].
Neurologic
Most reported individuals had congenital microcephaly, predominantly 2-3 SD below the mean; 5 SD below the mean was observed in one child [Accogli et al 2018].
Epilepsy. Two affected individuals were reported to have seizures; seizure type and severity was not specified [Elmas et al 2019, Mattioli et al 2019].
Neuroimaging. Ventriculomegaly was reported prenatally in four individuals [Casey et al 2016, Accogli et al 2018, Elmas et al 2019, Mattioli et al 2019] and in six affected individuals in total [Amos et al 2017, Nair et al 2018].
- One child had postnatal hydrocephalus that required ventriculoperitoneal shunt placement [Mattioli et al 2019].
- One individual had compensated supratentorial hydrocephalus due to aqueductal stenosis and was also reported to have cerebellar hypoplasia with severe vermian dysgenesis, small pons, hippocampal dysgenesis, and partial agenesis of the septum pellucidum [Accogli et al 2018].
Corpus callosum dysgenesis was identified in five reported individuals [Amos et al 2017, Mattioli et al 2019, Bruel et al 2019, Elmas et al 2019].
Growth
Low birth weight was present in most reported individuals, and intrauterine growth restriction was documented in four [Casey et al 2016, Amos et al 2017, Accogli et al 2018, Mattioli et al 2019].
Five individuals had failure to thrive in childhood [Anazi et al 2016, Accogli et al 2018, Gupta et al 2020, Zhang et al 2020].
Eight reported individuals were of short stature, in the range of 2-3 SD below the mean.
Gastrointestinal Problems
Three individuals presented with feeding difficulties, two requiring feeding through a gastrotomy tube because of inadequate caloric intake by mouth [Casey et al 2016, Mattioli et al 2019]. Three individuals had anal anomalies, including anal atresia, anteriorly positioned anus, and a rectoperineal fistula [Anazi et al 2016, Amos et al 2017, Accogli et al 2018]. One affected child was reported to have had a mesenteric cyst that required surgical correction [Zhang et al 2020].
Facial Features
Dysmorphic facial features were present in most reported individuals and included the following: tall forehead, deep-set eyes, short and upslanted palpebral fissures, epicanthal folds, and long nose with low-hanging columella (Figure 1). Facial features are typically not striking enough to allow a clinician to recognize the condition on this basis alone; however, the features are often recognized as consistent with this diagnosis after the diagnosis has been suggested or confirmed.
Figure 1.
Photographs of individuals with THOC6 intellectual disability syndrome showing the following facial dysmorphisms: tall forehead, high anterior hairline, deep-set eyes with short and upslanted palpebral fissures, long nose, low-hanging columella, and thick (more...)
Sensory Impairment
Hearing loss was reported in three affected individuals, and was specified to be of sensorineural origin in one [Amos et al 2017, Mattioli et al 2019].
Eyes. Myopia was noted in three individuals [Boycott et al 2010, Gupta et al 2020].
Other reported ocular anomalies include bilateral optic disc hypoplasia [Accogli et al 2018] and alternating exotropia, nystagmus, and hyperopia [Mattioli et al 2019].
ENT/Mouth
Micro-/retrognathia, reported in five individuals, was not significant enough to cause respiratory impairment [Boycott et al 2010, Amos et al 2017, Mattioli et al 2019].
Palatal anomalies. A cleft palate and a submucous cleft palate were seen in two individuals; one of them also had choanal atresia [Amos et al 2017, Mattioli et al 2019]. A bifid uvula and velopharyngeal insufficiency were reported in one individual each [Boycott et al 2010, Accogli et al 2018].
Teeth anomalies. Multiple dental caries and/or dental malocclusion were observed in ten affected individuals. Supernumerary teeth were also reported in one child [Accogli et al 2018].
Cardiovascular Anomalies
Atrial septal defect, ventricular septal defect, and patent ductus arteriosus were present in eight reported individuals. A dysmorphic and mildly insufficient mitral valve was also seen in one individual [Accogli et al 2018], and pulmonary hypertension in another [Mattioli et al 2019].
Genital Anomalies / Puberty
Males
- Cryptorchidism, bilateral or unilateral, was present in seven affected males.
- Two males presented with a micropenis [Nair et al 2018, Mattioli et al 2019], and one of them also had a hypospadias [Mattioli et al 2019].
Females
- Premature ovarian failure was identified in one teenage girl [Boycott et al 2010].
- Hypergonadotropic hypogonadism with primary amenorrhea requiring hormone replacement therapy was reported in another girl [Accogli et al 2018].
- Endometriosis was reported in one female [Boycott et al 2010].
Renal Anomalies
Unilateral renal agenesis was identified in four individuals [Beaulieu et al 2013, Casey et al 2016, Gupta et al 2020]. One of the individuals with unilateral renal agenesis also had a contralateral echogenic and atrophic kidney. She developed renal failure requiring dialysis at age 13 years and underwent kidney transplantation at age 15 years [Beaulieu et al 2013].
An ectopic kidney located in the pelvis or a horseshoe kidney was reported in three individuals [Beaulieu et al 2013, Accogli et al 2018, Gupta et al 2020].
Recurrent urinary tract infections were seen in three individuals [Boycott et al 2010, Amos et al 2017].
Skeletal Features
Cervical hemivertebrae and multilevel vertebral segmentation defects causing a scoliosis were reported in two different individuals [Accogli et al 2018, Gupta et al 2020].
Two individuals presented with camptodactyly [Anazi et al 2016, Accogli et al 2018].
Other reported anomalies include pes planus, trigger thumb, calcaneovalgus and equinovarus deformities, cubitus valgus, congenital hip dislocation, radioulnar joint dysostosis, cervical rib, and Sprengel deformity.
Prognosis
It is unknown whether life span in THOC6 intellectual disability syndrome is shortened. The original four affected individuals are now young adults, with the oldest in their early 40s [Author, personal communication], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
Prevalence
As of early 2020, seven years after this syndrome was first described and molecularly explained, 19 affected individuals have been reported in the literature.
Initially reported in the Hutterite population [Boycott et al 2010], THOC6 intellectual disability syndrome has now been identified in individuals worldwide. This disorder was more prevalent in two Hutterite leuts, with a specific founder variant (c.136G>A;p.Gly46Arg) frequency of 3% in Dariusleut controls and of 2% in Lehrerleut controls (see Molecular Genetics) [Beaulieu et al 2013].
Differential Diagnosis
Several intellectual disability disorders are associated with additional features that overlap those observed in THOC6 intellectual disability syndrome (see Table 3).
However, because the phenotypic features associated with THOC6 intellectual disability syndrome can be nonspecific, all disorders with intellectual disability (ID) without other distinctive findings should be considered in the differential diagnosis. To date more than 180 such disorders have been identified. See OMIM Phenotypic Series: Autosomal dominant ID; Autosomal recessive ID; Nonsyndromic X-linked ID; and Syndromic X-linked ID.
Table 3.
Genes of Interest in the Differential Diagnosis of THOC6 Intellectual Disability Syndrome
| Gene(s) | Disorder | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/THOC6 ID syndrome | Distinguishing from THOC6 ID syndrome | |||
| ATR CENPJ CEP152 CEP63 DNA2 NIN NSMCE2 RBBP8 TRAIP | Seckel syndrome (OMIM PS210600) | AR | ID; microcephaly; dental malocclusion | Severe growth restriction; characteristic facies |
| CREBBP EP300 | Rubinstein-Taybi syndrome | AD 1 | ID; microcephaly; genitourinary anomalies; low-hanging columella | Broad angulated thumbs & halluces; downslanting palpebral fissures & grimacing smile |
| EMG1 | Bowen-Conradi syndrome (OMIM 211180) | AR | Severe ID, microcephaly, & micrognathia; founder effect in Hutterite population | Multiple joint contractures; severe growth restriction; early mortality |
| KIF7 | Acrocallosal syndrome (OMIM 200990) | AR | Severe ID; corpus callosum dysgenesis; genital anomalies | Distal anomalies of limbs; macrocephaly w/protruding forehead & occiput |
| ZEB2 | Mowat-Wilson syndrome | AD 1 | Severe ID; microcephaly; corpus callosum dysgenesis; genitourinary anomalies; congenital heart defects | Hirschsprung disease or chronic constipation; distinctive facial features (uplifted earlobes, widely spaced eyes, prominent & pointed chin) |
AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance
- 1.
Typically the result of a de novo dominant pathogenic variant
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with THOC6 intellectual disability syndrome, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 4.
Recommended Evaluations Following Initial Diagnosis in Individuals with THOC6 Intellectual Disability Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Development | Developmental assessment |
|
| Psychiatric/ Behavioral | Neuropsychiatric eval | For persons age >12 mos: screening for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD |
| Neurologic | Neurologic eval |
|
| Gastrointestinal/ Feeding | Gastroenterology / nutrition / feeding team eval |
|
| Assess for anal anomalies. | Consider referral to a gastroenterology specialist or surgeon, as appropriate. | |
| Hearing | Audiologic eval | Assess for hearing loss. |
| Eyes | Ophthalmologic eval | Assess for reduced vision, abnormal ocular movement, & strabismus. |
| ENT/Mouth | Teeth & palate eval | Assess for dental caries, dental malocclusion, & cleft palate / velopharyngeal insufficiency. |
| Cardiovascular | Echocardiogram | Assess for congenital heart defects. |
| Genital | External genitalia exam, esp in males | Assess for cryptorchidism, hypospadias, or other genital anomalies. |
| Endocrine | Eval of secondary sexual characteristics & menstruation cycles in adolescent & adult females | Assess for primary amenorrhea or signs of premature ovarian failure. |
| Renal | Renal ultrasound |
|
| Musculoskeletal | Orthopedics / physical medicine & rehab / PT/OT eval | Incl assessment of:
|
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor | Incl genetic counseling |
| Family support/resources | Assess:
|
ADLs = activities of daily living; OT = occupational therapy; PT = physical therapy
- 1.
Such as blood urea nitrogen (BUN), creatinine, and urinalysis
Treatment of Manifestations
Table 5.
Treatment of Manifestations in Individuals with THOC6 Intellectual Disability Syndrome
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Developmental delay / Intellectual disability | See Developmental Delay / Intellectual Disability Management Issues. | |
| Hydrocephalus / Cerebral malformations | Standard treatment(s) as recommended by neurologist/neurosurgeon | |
| Epilepsy | Standardized treatment w/AEDs by experienced neurologist |
|
| Poor weight gain / Failure to thrive |
| Low threshold for clinical feeding eval & |