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WAC-Related Intellectual Disability

, MD, , MD, PhD, and , PhD.

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Estimated reading time: 20 minutes

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 1MethodProportion of Probands with a Pathogenic
Variant 2 Detectable by Method
WACSequence analysis 317/18 4
Gene-targeted deletion/duplication analysis 5, 61/18 7
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.

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.

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:

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

DisorderGene/Genetic MechanismMOIClinical Features of the Differential Diagnosis Disorder
Overlapping w/WAC-Related IDDistinguishing from WAC-Related ID
Prader-Willi syndrome 1Abnormal parent-specific imprinting within the Prader-Willi critical regionSee footnote 2
  • Hypotonia, feeding difficulties in early infancy
  • Delayed motor milestones & language development
Obesity & food-seeking behaviors typically not a feature of WAC-related ID
Smith-Magenis syndrome 3Deletion or mutation of RAI1 on chromosome 17p11.2 4Virtually all de novoNeonatal hypotonia w/feeding difficulties, DD & ID, & some behavioral disturbances (incl abnormal sleep patterns) 5Some characteristic behaviors (e.g., self-hugging, polyembolokoilamania)
Pitt-Hopkins syndromeHaploinsufficiency of TCF4Most de novo
  • DD & ID; sleep disturbances, seizures, constipation
  • Facial features incl deep-set eyes & wide mouth w/prominence of the lower face
  • Abnormal breathing pattern (seen in 2 individuals w/WAC-related ID) 6
ID usually more severe
Angelman syndrome 5Disruption of maternally imprinted UBE3ASee footnote 7
  • DD, ID, sleep disorders
  • Seizures variably present in both (rare in WAC-related ID)
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 8Almost all de novo
  • Neonatal/childhood hypotonia & DD w/associated ID
  • Abnormal vision, epilepsy, & renal anomalies variably seen in both disorders (rare in WAC-related ID; in ~50% w/KANSL1-related ID
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/ConcernEvaluationComment
GrowthAssessment of growth parameters to identify those w/failure to thrive
OphthalmologyOphthalmology evaluation
ENTAudiology evaluation when clinical history is suggestive of a hearing problemIf abnormal, refer to otolaryngologist
Gastroenterology/
Feeding
Baseline evaluation for presence of reflux and/or constipation; assessment for feeding problemsIf needed, refer to gastroenterologist &/or feeding therapist for treatment
RespiratoryRespiratory assessment when clinical history indicates presence of recurrent infections &/or asthmaIf abnormal, refer to pulmonologist
GenitourinaryRenal ultrasound examination when clinical history is suggestive of a renal problemIf 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 ASDConsider referral for formal testing, incl Autism Diagnostic Interview™ & Autism Diagnostic Observation Schedule™
NeurologicAssess 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 skillsReferral 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/ConcernTreatment
Recurrent infections and/or asthmaStandard treatment(s) as recommended by pulmonologist
Poor weight gain / failure to thriveFeeding therapy; gastrostomy tube placement may be required for persistent feeding issues 1
Gastroesophageal reflux disease and/or constipationStandard treatment(s)
SeizuresStandard treatment(s) as recommended by neurologist
Abnormal vision and/or strabismusStandard treatment(s) as recommended by ophthalmologist
Renal abnormalitiesStandard 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/ConcernEvaluation 1
EyesOphthalmologic evaluation
ENT/MouthAudiologic evaluation
GastrointestinalRegular dietary evaluation in infancy to ensure optimal nutritional status
GenitourinaryMonitor those w/renal abnormalities as clinically indicated
NeurologicMonitor those w/seizures as clinically indicated
PsychiatricBehavioral assessment for anxiety, attention, & aggressive or self-injurious behavior
Miscellaneous/OtherMonitor developmental progress & educational needs
1.

The frequency with which each evaluation or reassessment occurs should be tailored to the needs of the affected individual.

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

WAC-related intellectual disability is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If the WAC pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. One such case of recurrence due to presumed parental germline mosaicism has been reported [DeSanto et al 2015].
  • If the parents have not been tested for the WAC pathogenic variant but are thought to be clinically unaffected, risk to sibs appears to be low but is still increased over that of the general population because of the possibility of a less severe, undiagnosed presentation in a parent or germline mosaicism in a parent.

Offspring of a proband

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the WAC 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 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.

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.

WAC-Related Intellectual Disability: Genes and Databases

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 WAC-Related Intellectual Disability (View All in OMIM)

615049WW DOMAIN-CONTAINING ADAPTOR WITH COILED-COIL REGION; WAC
616708DESANTO-SHINAWI SYNDROME; DESSH

Gene structure. The longest WAC transcript variant NM_016628.4 consists of 14 exons encoding for 647 amino acids. Alternative splicing events yield at least two additional transcript variants of WAC: NM_100264.2 and NM_100486.3. See Table A, Gene for details.

Benign variants. Three presumably loss-of-function variants have been reported in the Exome Aggregation Consortium (ExAC) dataset [Lek et al 2016]. Each has been found in one individual among the specific population cohorts. Lugtenberg et al [2016] commented that these variants (all of which represent insertion/deletion events) may represent sequencing artifacts not validated by Sanger sequencing or could represent the mild end of the intellectual disability (ID) spectrum in the general population.

As also explicitly stated for at least some of these databases, attempts have been made to exclude individuals with severe pediatric diseases – which may not be the case for less severe phenotypes [Lek et al 2016].

Pathogenic variants. WAC pathogenic variants reported include 15 variants that predict loss of function (nonsense variants or small deletions or insertions) and one intragenic multiexon deletion [Lugtenberg et al 2016] (see Table 1). To date no missense variants have been reported in individuals with WAC-related ID.

The smallest region of overlap among 11 deletions of 10p12.1 is an 80-kb region containing only WAC, supporting a haploinsufficiency mechanism for WAC-related ID [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 ID or additional features (e.g., cardiac anomalies) due to haploinsufficiency of other genes.

One frameshift variant (c.1885_1886delTT) reported by Lugtenberg et al [2016] in an individual with WAC-related ID is presumed to escape nonsense-mediated decay.

One variant (c.1648C>T) was found in two unrelated individuals with mild and moderate ID [Lugtenberg et al 2016].

Table 6.

WAC Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1648C>T 1p.Arg550TerNM_016628​.4
NP_057712​.2
c.1885_1886delTTp.Leu629GlufsTer5

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.

Normal gene product. The protein encoded by WAC contains a WW domain and a coiled-coiled region. The WW domain, a protein module mediating protein-protein interactions, is found in a wide range of signaling proteins. Although the exact function of WAC is unknown, it has been suggested that it acts as a functional partner of RNF20/40, which has been shown to regulate histone H2B ubiquitination, a process regulating chromatin organization during transcription [Zhang & Yu 2011]. WAC also co-localizes with splicing factor SC35, a finding that could suggest a role in RNA processing [Xu & Arnaout 2002]. See Lugtenberg et al [2016] on the presumed role of WAC.

Abnormal gene product. Haploinsufficiency resulting from inactivation of one WAC allele is the cause of WAC-related ID.

References

Literature Cited

  • Abdelhedi F, El Khattabi L, Essid N, Viot G, Letessier D, Lebbar A, Dupont JM. A de novo 10p11.23-p12.1 deletion recapitulates the phenotype observed in WAC mutations and strengthens the role of WAC in intellectual disability and behavior disorders. Am J Med Genet A. 2016;170:1912–7. [PubMed: 27119754]
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Chapter Notes

Revision History

  • 30 November 2017 (bp) Review posted live
  • 17 February 2017 (kv) Original submission
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