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 testing are possible.

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 (or likely pathogenic) variant in WAC on molecular genetic testing (see Table 1).

Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

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 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.

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 affected individuals, 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 intellectual disability Female 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.

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 [Fitzgerald et al 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.

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).

Treatment of Manifestations

Treatment can include the following.

Surveillance

The following are appropriate.

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.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• To date, vertical transmission of WAC-related ID from an affected parent to a proband has not been reported.
• With the exception of one family with presumed parental germline mosaicism [DeSanto et al 2015], all individuals diagnosed to date with WAC-related ID have the disorder as the result of a de novo pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the most likely explanation is a de novo variant in the proband. Parental germline mosaicism, presumed to have occurred in one reported family, is another possible explanation [DeSanto et al 2015].
• The family history of some individuals diagnosed with WAC-related ID may appear to be negative because 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.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

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 as a result of 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

• Each child of an individual with WAC-related ID has a 50% chance of inheriting the WAC pathogenic variant.
• The degree of severity in offspring who inherit a WAC pathogenic variant cannot be predicted as clinical variability has been observed in affected sibs and in unrelated individuals with the same WAC pathogenic variant (see Genotype-Phenotype Correlations).

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, the parent's 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/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Revision History

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

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