Clinical Guidance

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 intellectual disability was mild in one and moderate in the other .

• 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 .

Source: GeneReviews — "WAC-Related Intellectual Disability"

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.

Source: GeneReviews — "WAC-Related Intellectual Disability"

Diagnostic Criteria

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:

Source: GeneReviews — "WAC-Related Intellectual Disability"

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 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

Management Guidelines

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 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

Source: GeneReviews — "WAC-Related Intellectual Disability"

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.

Source: GeneReviews — "WAC-Related Intellectual Disability"

Surveillance Guidelines

The following are appropriate.

Table 5.

Recommended Surveillance for Individuals with WAC-Related Intellectual Disability

System/Concern | Evaluation1

Eyes | Ophthalmologic eval

ENT/Mouth

| Audiologic eval

Gastrointestinal

| Regular dietary eval 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

| Monitor developmental progress educational needs.

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

Source: GeneReviews — "WAC-Related Intellectual Disability"