Wac-Related Intellectual Disability
Summary
Clinical characteristics.
WAC-related intellectual disability (ID) is typically characterized by variable degrees of developmental delay and/or intellectual disability. Behavioral abnormalities including anxiety, attention-deficit/hyperactivity disorder, and/or autism spectrum disorder are observed in the majority of older children and adults. Most affected infants have significant but nonspecific features at birth such as neonatal hypotonia and feeding problems. Some affected individuals come to medical attention with respiratory or vision problems. Facial features may be mildly dysmorphic, but are nonspecific. To date, 18 individuals have been identified with WAC-related ID.
Diagnosis/testing.
The diagnosis of WAC-related ID is established in a proband by identification of a heterozygous pathogenic variant in WAC on molecular genetic testing.
Management.
Treatment of manifestations: Standard treatment of developmental delay / intellectual disability, behavioral abnormalities, neonatal hypotonia, and feeding problems.
Surveillance: Regular dietary evaluation in infancy to ensure optimal nutritional status; routine monitoring of developmental progress and educational needs; assessment for anxiety, attention, and aggressive or self-injurious behavior.
Genetic counseling.
WAC-related ID is inherited in an autosomal dominant manner. With the exception of one family with presumed parental germline mosaicism, all individuals diagnosed to date have the disorder as the result of a de novo pathogenic variant. Once the WAC 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 exist for WAC-related intellectual disability.
Suggestive Findings
WAC-related intellectual disability (ID) should be considered in individuals with SOME OR ALL of the following suggestive findings:
- Developmental delay or variable degrees of intellectual disability
- One or more of the following:
- Generalized hypotonia in infancy with or without associated oral hypotonia
- Neonatal feeding difficulties, gastroesophageal reflux, and/or constipation
- Behavioral abnormalities including anxiety, attention-deficit/hyperactivity disorder (ADHD), aggression, sleep disturbances, and autism spectrum disorder (ASD)
- Respiratory problems: recurrent infections, asthma, and/or abnormal breathing pattern
- Abnormal vision including cortical visual impairment, strabismus, and refractive errors
Other less specific features that may prompt further consideration of this diagnosis include:
- Seizures
- Abnormalities of the extremities including brachydactyly, presence of fetal finger pads, and planovalgus deformity of the feet
- Inverted nipples
Establishing the Diagnosis
The diagnosis of WAC-related ID is established in a proband by identification of a heterozygous pathogenic variant in WAC on molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of genomic testing (comprehensive genomic 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 may not. Because the phenotypes of inherited intellectual disability overlap, most individuals with WAC-related ID are diagnosed by the following recommended testing or testing to be considered.
Recommended testing options to consider
- A multigene panel that includes WAC 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 WAC-related intellectual disability, 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.
- Comprehensive genomic testing (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 WAC, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.
Table 1.
Molecular Genetic Testing Used in WAC-Related Intellectual Disability
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| WAC | Sequence analysis 3 | 17/18 4 |
| Gene-targeted deletion/duplication analysis 5, 6 | 1/18 7 |
- 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. 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.
Hamdan et al [2014], DeSanto et al [2015], Tammimies et al [2015], Lugtenberg et al [2016]. See Molecular Genetics, Pathogenic variants.
- 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.
- 6.
Individuals reported to have larger deletions that include more genes in the 10p12.1 region have phenotypic features that overlap those of WAC-related intellectual disability described in this GeneReview [Shahdadpuri et al 2008, Wentzel et al 2011, Okamoto et al 2012, Mroczkowski et al 2014, Sosoi et al 2015, Abdelhedi et al 2016]. Larger deletions may, however, be associated with more severe degrees of intellectual disability or additional features (such as cardiac anomalies) due to haploinsufficiency of other genes.
- 7.
To date, one individual has been reported with an intragenic deletion encompassing exons 5 to 14 (originally detected by CMA) [Lugtenberg et al 2016].
Clinical Characteristics
Clinical Description
WAC-related intellectual disability is typically characterized by variable degrees of developmental delay and/or intellectual disability. Behavioral abnormalities including anxiety, attention-deficit/hyperactivity disorder, and/or autism spectrum disorder are observed in the majority of older children and adults. Most affected infants have significant but nonspecific features at birth such as neonatal hypotonia and feeding problems. Some affected individuals come to medical attention because of respiratory or vision problems; constipation is common. Although facial features may be mildly dysmorphic, they may not be observed universally and/or are often not specific enough to allow diagnosis.
To date, 18 individuals have been identified with a pathogenic variant in WAC [Hamdan et al 2014, DeSanto et al 2015, Tammimies et al 2015, Lugtenberg et al 2016].
Most Commonly Seen Features
Hypotonia. More than 75% of the infants (14 of 17 for whom this information was available) have significant hypotonia at birth and during infancy which may be the clinical finding for which they are initially evaluated. Oral hypotonia may contribute to the feeding difficulties as well as to speech delay.
Neonatal feeding difficulties have been reported in approximately 45% (7/16) of individuals with WAC-related ID. In addition to the hypotonia, gastroesophageal reflux was reported in two children and swallowing difficulties in one. The feeding difficulties are typically managed with oral feedings; only one child was dependent on a G-tube.
Developmental delay and intellectual disability. Delay in attainment of speech and/or motor milestones is a universal feature.
While the preliminary information available does not allow firm conclusions, approximately two thirds of the individuals reported to date are nonverbal at age 18 months. Although severe speech delay does not seem to be the rule, a few children remained nonverbal at age four years (and in some cases beyond). Dysarthria secondary to oral hypotonia was reported in some [Lugtenberg et al 2016].
Variable degrees of both fine motor and gross motor delay have been observed in almost all individuals for whom this information is available. Walking was achieved after age 21 months in the majority. Fine motor development may be equally affected as some individuals have been reported to have poor hand dexterity or clumsiness and difficulty in global coordination.
Intellectual disability, which appears to be present in the majority of affected individuals, is typically in the mild end of the spectrum and was only observed in the moderate-to-severe range in fewer than 20% (3/18). Of note, on formal IQ testing two individuals had results within the normal range (full-scale IQ scores 98 [DeSanto et al 2015] and 89 [Lugtenberg et al 2016]); both had had abnormal prior development, and the latter had a formal diagnosis of autism spectrum disorder. Two additional individuals had borderline intellectual functioning.
Behavioral problems of any type are present in more than 80% (15/16) of affected individuals. Sleep disturbances, reported in approximately two thirds of individuals, are among the most common. Although poorly characterized, frequent night awakenings appeared to be a problem in at least two individuals.
Attention-deficit/hyperactivity disorder and anxiety have been observed in 30%-40% of individuals.
Approximately 20% of reported individuals had a formal diagnosis of autism spectrum disorder (ASD). Autistic traits were reported in one individual.
Aggressive and self-injurious behavior was reported in a few individuals.
Abnormal vision. More than half of affected individuals had vision problems. Refractive errors as well as strabismus have been reported on several occasions, the latter in approximately one third of affected individuals. In a few individuals with poor vision of unknown cause, the cause was attributed to cortical visual impairment.
Gastrointestinal problems. Bowel dysmotility mainly manifest as constipation was observed in approximately one third (5/16) of individuals. Gastroesophageal reflux disease has been observed on occasion. Because the presence of gastrointestinal problems has not been systematically evaluated in all patients, the actual prevalence may be higher.
Respiratory abnormalities, a feature in approximately 40% of reported individuals, included recurrent infections (5 individuals), asthma (2 occasions), and an abnormal breathing pattern (2 individuals) [Lugtenberg et al 2016]. Because the presence of respiratory abnormalities has not been evaluated consistently in the available reports, the actual prevalence may be higher.
Facial gestalt. The most frequent features are a square-shaped face with a broad or prominent forehead, deeply set eyes with long palpebral fissures, broad or depressed nasal bridge, and wide mouth with a broad chin. Other features that may be observed include synophrys, hypertelorism, epicanthus, and bulbous nose or broad nasal tip. See Figure 1. Although DeSanto et al [2015] argue that loss-of-function pathogenic variants in WAC are associated with a recognizable phenotype, the facial features may not be observed universally and/or are often not specific enough to allow diagnosis.
Figure 1.
Three individuals with WAC-related ID Female at age 19 years (1)
Minor ear anomalies have been described in 50% of affected individuals (8/16), including posteriorly rotated ears and prominence of the antihelix (most commonly of the stem, although the superior and inferior crus can also be prominent).
Neuroimaging.While abnormal MRI findings have been observed in seven individuals with WAC-related ID, no consistent abnormality has been observed. Ventriculomegaly and prominence/enlargement of subarachnoid spaces have each been reported on two occasions. Other findings (each reported in 1 individual) include asymmetry of the hemispheres and a retrocerebellar arachnoid cyst.
Features Reported in 10%-30% of Affected Individuals
Seizures were observed in four of 17 reported individuals. The following were each reported in one individual:
- Tonic-clonic seizures
- Absence episodes
- Seizure-like activity
- Febrile convulsions
Obesity, reported in three of 18 individuals, was reported to be truncal in one individual; no details were provided on the other two.
Hearing loss, reported in two of 18, was inconsistent (1 had sensorineural hearing loss and 1 had conductive hearing loss) [DeSanto et al 2015].
Nonspecific kidney problems included:
- Mild unilateral renal caliectasis in one individual and right pelvic kidney in another [DeSanto et al 2015];
- A girl age nine years with unspecified kidney problems [Lugtenberg et al 2016].
Other
- Foot abnormalities. Usually plano-valgus deformity
- Hand abnormalities. Brachydactyly, presence of fetal finger pads, short hands, unilateral single tranverse palmar crease
- Inverted nipples
Genotype-Phenotype Correlations
To date only loss-of-function WAC variants have been reported in individuals with WAC-related intellectual disability. The small number of reported individuals is not sufficient to draw conclusions about genotype-phenotype correlations.
Variability in intellectual function has been observed in individuals with the same WAC variant:
- In two unrelated individuals with the variant c.1648C>T intellectual disability was mild in one and moderate in the other [Lugtenberg et al 2016].
- In two sibs with the same variant, intellectual functioning was borderline in one and normal in the other, who (despite a full-scale IQ score of 98) was reported to perform below average in some verbal and nonverbal skills (e.g., confrontation naming or spatial orientation) and to score low in evaluation of motor function [DeSanto et al 2015].
Nomenclature
WAC-related intellectual disability is also referred to as DeSanto-Shinawi syndrome (DESSH).
Penetrance
To date all individuals with WAC-related intellectual disability have the disorder as the result of a de novo pathogenic variant or germline mosaicism. Based on the published cases, the penetrance is complete (100%). Reliable estimates on the penetrance of the disorder are however difficult to establish given that most affected individuals have been identified through the discovery of a de novo and/or loss-of-function variant in WAC.
Prevalence
To date, 18 individuals with WAC-related intellectual disability (ID) have been reported in the literature.
In each of the following cohorts of children with ID and/or autism spectrum disorder (ASD), one child was found to have a de novo WAC pathogenic variant:
- One of 1,133 children with severe, undiagnosed, developmental disorders [Deciphering Developmental Disorders Study 2015]. Of note, children with easily recognized syndromes or large pathogenic copy number variants identified in prior genetic testing were excluded from this study.
- One of 258 unrelated children with ASD, all of whom were initially tested by chromosomal microarray analysis and 95 of whom were further investigated by trio exome sequencing (i.e., exome sequencing of the proband and both parents) [Tammimies et al 2015]
The prevalence of WAC-related ID may, however, be difficult to establish given the under-ascertainment of less severely affected individuals, the ascertainment bias for individuals with de novo or loss-of-function variants, and the genetic testing modalities implemented for prior exclusion of affected individuals in the evaluation of cohorts with ID/ASD.
Differential Diagnosis
Developmental delay, neonatal feeding difficulties, and hypotonia, the most frequent features in WAC-related intellectual disability, are relatively common and have an extensive differential diagnosis.
The syndromes in Table 2 show significant phenotypic overlap with WAC-related ID and have been considered in affected individuals before the diagnosis of WAC-related ID was established.
Table 2.
Disorders to Consider in the Differential Diagnosis of WAC-Related Intellectual Disability
| Disorder | Gene/Genetic Mechanism | MOI | Clinical Features of the Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/WAC-Related ID | Distinguishing from WAC-Related ID | |||
| Prader-Willi syndrome 1 | Abnormal parent-specific imprinting within the Prader-Willi critical region | See footnote 2 |
| Obesity & food-seeking behaviors typically not a feature of WAC-related ID |
| Smith-Magenis syndrome 3 | Deletion or mutation of RAI1 on chromosome 17p11.2 4 | Virtually all de novo | Neonatal hypotonia w/feeding difficulties, DD & ID, & some behavioral disturbances (incl abnormal sleep patterns) 5 | Some characteristic behaviors (e.g., self-hugging, polyembolokoilamania) |
| Pitt-Hopkins syndrome | Haploinsufficiency of TCF4 | Most de novo |
| ID usually more severe |
| Angelman syndrome 5 | Disruption of maternally imprinted UBE3A | See footnote 7 |
| Usually nonverbal, w/more severe ID |
| KANSL1-related intellectual disability syndrome (Koolen-deVries syndrome) | 500- to 650-kb heterozygous deletion at chromosome 17q21.31 incl KANSL1 or a heterozygous KANSL1 intragenic pathogenic variant 8 | Almost all de novo |
| Characteristic facial gestalt (incl. upslanting palpebral fissures, tubular/pear shaped nose w/bulbous nasal tip & prominent ears) |
DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance
- 1.
One individual reported by DeSanto et al [2015] reportedly had PWS testing.
- 2.
The risk to the sibs of an affected child of having PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region.
- 3.
Among the ten individuals with WAC-related ID reported by Lugtenberg et al [2016], three had had normal RAI1 testing prior to establishing the correct diagnosis.
- 4.
Approximately 95% of individuals with Smith-Magenis syndrome have the disorder as a result of an interstitial 17p11.2 deletion, which may have been previously excluded by chromosomal microarray testing.
- 5.
Two individuals reported by Lugtenberg et al [2016] had been previously tested for Angelman syndrome.
- 6.
One individual reported by Lugtenberg et al [2016] had previously undergone TCF4 testing.
- 7.
The risk to sibs of a proband depends on the genetic mechanism leading to the loss of UBE3A function.
- 8.
KANSL1-related ID syndrome is, on most occasions, readily diagnosed by detection of the typical 17q21.31 microdeletion on chromosomal microarray. Note: The 17q21.31 microdeletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.
Management
Evaluations and Referrals Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with WAC-related intellectual disability, the evaluations and referrals outlined in Table 3 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 autism spectrum disorder [ASD] in an infant).
Table 3.
Recommended Evaluations and Referrals Following Initial Diagnosis of WAC-Related Intellectual Disability
| System/Concern | Evaluation | Comment |
|---|---|---|
| Growth | Assessment of growth parameters to identify those w/failure to thrive | |
| Ophthalmology | Ophthalmology evaluation | |
| ENT | Audiology evaluation when clinical history is suggestive of a hearing problem | If abnormal, refer to otolaryngologist |
| Gastroenterology/ Feeding | Baseline evaluation for presence of reflux and/or constipation; assessment for feeding problems | If needed, refer to gastroenterologist &/or feeding therapist for treatment |
| Respiratory | Respiratory assessment when clinical history indicates presence of recurrent infections &/or asthma | If abnormal, refer to pulmonologist |
| Genitourinary | Renal ultrasound examination when clinical history is suggestive of a renal problem | If abnormal, refer to nephrologist |
| Psychiatric/ Behavioral | For individuals age >12 mos: clinical screening for presence of behavior problems incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD | Consider referral for formal testing, incl Autism Diagnostic Interview™ & Autism Diagnostic Observation Schedule™ |
| Neurologic | Assess for possible seizure activity. | If present, consider an EEG &/or referral to neurologist |
| Miscellaneous/ Other | Multidisciplinary developmental evaluation incl motor, speech/language evaluation, general cognitive, & vocational skills | Referral to developmental pediatrician &/or developmental psychologist |
| Consultation w/clinical geneticist &/or genetic counselor |
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
Treatment of Manifestations
Treatment can include the following.
Table 4.
Treatment of Manifestations in Individuals with WAC-Related Intellectual Disability
| Manifestation/Concern | Treatment |
|---|---|
| Recurrent infections and/or asthma | Standard treatment(s) as recommended by pulmonologist |
| Poor weight gain / failure to thrive | Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues 1 |
| Gastroesophageal reflux disease and/or constipation | Standard treatment(s) |
| Seizures | Standard treatment(s) as recommended by neurologist |
| Abnormal vision and/or strabismus | Standard treatment(s) as recommended by ophthalmologist |
| Renal abnormalities | Standard treatment(s) as recommended by nephrologist |
- 1.
Diet diary and calorie counts may be requested.
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 by 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 individualized education program (IEP) can be developed by the local public school district based on each individual's level of function. 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 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 alternative means of communication for individuals who have expressive language difficulties, such as an Augmentative and Alternative Communication (AAC) evaluation.
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.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used 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.
Table 5.
Recommended Surveillance for Individuals with WAC-Related Intellectual Disability
| System/Concern | Evaluation 1 |
|---|---|
| Eyes | Ophthalmologic evaluation |
| ENT/Mouth | Audiologic evaluation |
| Gastrointestinal | Regular dietary evaluation in infancy to ensure optimal nutritional status |
| Genitourinary | Monitor those w/renal abnormalities as clinically indicated |
| Neurologic | Monitor those w/seizures as clinically indicated |
| Psychiatric | Behavioral assessment for anxiety, attention, & aggressive or self-injurious behavior |
| Miscellaneous/Other |