Wdr26-Related Intellectual Disability
Summary
Clinical characteristics.
WDR26-related intellectual disability (ID) is characterized by developmental delay / intellectual disability, characteristic facial features, hypotonia, epilepsy, and infant feeding difficulties. To date 15 individuals, ages 24 months to 34 years, have been reported. Developmental delay is present in all individuals and ranges from mild to severe. All individuals have delayed speech. Although some begin to develop speech in the second year, others have remained nonverbal. Seizures, present in all affected individuals reported to date, can be febrile or non-febrile (tonic-clonic, absence, rolandic seizures); most seizures are self limited or respond well to standard treatment. Affected individuals are generally described as happy and socially engaging; several have stereotypies / autistic features (repetitive or rocking behavior, abnormal hand movements or posturing, and at times self-stimulation).
Diagnosis/testing.
The diagnosis of WDR26-related ID is established in a proband with suggestive clinical features and a heterozygous pathogenic variant in WDR26 identified by molecular genetic testing.
Management.
Treatment of manifestations: Standard treatment of developmental delay / intellectual disability, seizures, infant feeding problems, and behavioral issues.
Surveillance: In infancy: regular assessment of swallowing, feeding, and nutritional status to determine safety of oral vs gastrostomy feeding. For all age groups: routine monitoring of developmental progress, educational needs, and behavioral issues.
Genetic counseling.
WDR26-related ID is inherited in an autosomal dominant manner. All individuals reported to date have the disorder as the result of a de novo pathogenic variant. If the WDR26 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Diagnosis
Formal diagnostic criteria for WDR26-related intellectual disability have not been established.
Suggestive Findings
WDR26-related intellectual disability should be considered in individuals with the following findings [Skraban et al 2017]:
- Developmental delay or intellectual disability of variable degree
- Characteristic facial features including coarse features, prominent eyes with large-appearing irises, prominent maxilla, broad nasal tip, protruding upper lip, prominent upper gingiva, and widely spaced teeth (Figure 1)
- Central hypotonia
- Autistic features
- Seizures: both febrile and non-febrile
- Abnormal wide-based, ataxic, and/or stiff-legged gait
Figure 1.
Four individuals with loss-of-function WDR26 variants. Characteristic facial features include coarse appearance, prominent eyes, prominent maxilla, broad nasal tip, protruding upper lip, prominent upper gingiva, and widely spaced teeth. Images published (more...)
Establishing the Diagnosis
The diagnosis of WDR26-related ID is established in a proband with suggestive clinical features and identification of a heterozygous pathogenic variant in WDR26 by molecular genetic testing (see Table 1).
Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability typically begins with chromosomal microarray analysis (CMA). If CMA is not diagnostic, the next step is typically either a multigene panel or comprehensive genomic testing (exome sequencing, genome sequencing). Note: Single-gene testing (sequence analysis of WDR26, followed by gene-targeted deletion/duplication analysis) is of unproven utility, and unless WDR26-related ID is strongly suspected, it is typically NOT recommended.
- Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays can identify chromosome 1q42 microdeletions that can include WDR26, causing WDR26-related ID (see Table 1).
- An intellectual disability (ID) multigene panel that includes WDR26 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. (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 this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- Comprehensive genomic testing, which does not require the clinician to determine which gene(s) are likely involved, is another option. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Note: To date such variants have not been reported as a cause of WDR26-related ID.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 WDR26-Related Intellectual Disability
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| WDR26 | Sequence analysis 3 | 15/15 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown; see footnote 6 | |
| Chromosomal microarray 7 | Unknown; see footnote 8 |
- 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.
Skraban et al [2017]
- 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.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
- 7.
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use include the 1q42region.
- 8.
To date, no individuals with isolated deletions of WDR26 identified by CMA have been reported.
Clinical Characteristics
Clinical Description
WDR26-related intellectual disability is characterized by developmental delay / intellectual disability, epilepsy, and infant feeding difficulties. To date 15 individuals (10 female, 5 male) with intragenic pathogenic variants in WDR26 have been reported; they range in age from 24 months to 34 years [Skraban et al 2017].
Developmental delay (DD) and intellectual disability (ID) are present in all individuals. Developmental delay ranges from mild in many to severe in approximately 30%. Sitting is delayed with an average of 11 months. Walking is delayed, with reported onset averaging 24 months but ranging from age 17 months to three years.
Speech development is a relative weakness. All individuals have delayed speech. Although some begin to develop speech in the second year, others remain nonverbal through childhood.
Seizures, described in all affected individuals reported to date, range in onset from the newborn period to age seven years.
Seizure types are generally mild and include febrile and non-febrile (tonic-clonic, absence, rolandic). Most are self limited or respond well to standard treatments.
Other neurodevelopmental features
- Hypotonia, present in nine of 12 reported individuals; typically mild
- Failure to thrive and infant feeding difficulties; reported in six of 15 individuals, with three requiring a gastrostomy tube at least temporarily
- An abnormal gait, described as wide-based, ataxic, and/or stiff-legged
- Structural brain anomalies, nearly all minor, noted in ten of 14 individuals; including the nonspecific findings (enlarged ventricles, thin corpus callosum, white matter volume loss, mild cerebellar hypoplasia, and pineal cyst) as well as a markedly abnormal left supratentorial hemisphere structure with pachygyria that required hemispherectomy (in 1 individual)
- Microcephaly; noted in three of 14 individuals
Behavior. Patients are generally described as happy and socially engaging. Several have stereotypies / autistic features including repetitive or rocking behavior, abnormal hand movements or posturing, and at times self-stimulation. Most prefer to engage with other children and adults rather than pursue solitary activities. While active, most children are directable and can concentrate on tasks and are not typically reported to be hyperactive.
Other features
- Ophthalmologic
- Strabismus and/or amblyopia (in 9/14)
- Congenital abducens paresis (in 1)
- Marcus Gunn jaw winking (in 1)
- Refractive errors, including myopia and hyperopia
- ENT
- Recurrent otitis media / eustachian tube dysfunction (5/15)
- Cleft palate (1)
- Respiratory abnormalities. Mild tracheomalacia (1)
- Gastrointestinal problems. Constipation (4/12) and gastroesophageal reflux (3/13)
- Musculoskeletal
- Mild contractures of the lower extremities (2)
- Pes cavus (2)
- Forefoot varus (1)
- Hip dysplasia (1)
- Osteopathia striata of the distal femurs (1)
- Cardiac
- Ventricular septal defect (1)
- Right-sided aortic arch (1)
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been established.
Nomenclature
WDR26-related intellectual disability has also been referred to as Skraban-Deardorff syndrome.
Prevalence
WDR26-related intellectual disability is rare. Only 15 individuals with intragenic pathogenic WDR26 variants have been reported to date. These 15 were identified among some 21,400 individuals with intellectual disability who had exome sequencing, giving an estimated frequency of 1:1,500 for individuals with unknown causes of intellectual disability [Skraban et al 2017].
Differential Diagnosis
Developmental delay with delayed speech and febrile and/or non-febrile seizures, the most frequent features of WDR26-related ID, are relatively common and have an extensive differential diagnosis.
The following syndromes with significant phenotypic overlap with WDR26-related ID have been considered in some affected individuals before the diagnosis of WDR26-related ID was established (Table 2).
Table 2.
Disorders with Developmental Delay / Intellectual Disability to Consider in the Differential Diagnosis of WDR26-Related Intellectual Disability
| Differential Diagnosis Disorder | Gene / Genetic Mechanism | MOI | Clinical Features of the Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/WDR26-related ID | Distinguishing from WDR26-related ID | |||
| Angelman syndrome | Deficient expression/ function of maternally inherited UBE3A allele | See footnote 1 |
|
|
| Pitt-Hopkins syndrome | TCF4 or deletion of the chromosome region in which TCF4 is located | See footnote 2 |
|
|
| Alpha-thalassemia X-linked intellectual disability syndrome | ATRX | XL |
|
|
| Kleefstra syndrome | EHMT1 or deletion at 9q34.3 | AD |
|
|
AD = autosomal dominant; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
- 1.
The risk to sibs of a proband depends on the genetic mechanism leading to the loss of UBE3A function: typically less than 1% risk for probands with a deletion or uniparental disomy, and as high as 50% for probands with an imprinting defect or a pathogenic variant of UBE3A.
- 2.
Pitt-Hopkins syndrome is caused by haploinsufficiency of TCF4. Most individuals reported to date have represented simplex cases (i.e., a single occurrence in a family) resulting from a de novo pathogenic variant or deletion.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with WDR26-related intellectual disability (ID), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with WDR26-Related ID
| System/Concern | Evaluation | Comment |
|---|---|---|
| Constitutional | Assessment of height, weight, head circumference | Evaluation of growth parameters to identify those w/FTT |
| Neurologic | Neurologic evaluation | Incl EEG & brain MRI if seizures |
| Development | Developmental assessment | Incl assessment of age-appropriate motor, speech/language, cognitive skills. |
| Eyes | Ophthalmologic evaluation | For evidence of refractive error, strabismus ± amblyopia, cataracts, abnormal extraocular movement |
| ENT/Mouth | Consultation w/ENT | For those w/:
|
| Cardiovascular | Consultation w/cardiologist | If evidence of congenital heart defect |
| Respiratory | Consultation w/pulmonologist | If evidence of tracheomalacia |
| Gastrointestinal/ Feeding | Gastroenterology / nutrition / feeding team evaluation | For those w/:
|
| Musculoskeletal | Consultation w/physiatrist | For those w/gait abnormalities |
| Psychiatric/ Behavioral | Neuropsychiatric evaluation | Screen individuals age >12 mos for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD. |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor |
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ENT = ear, nose, and throat; FTT = failure to thrive; GERD = gastroesophageal reflux disease
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with WDR26-Related Intellectual Disability
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| Feeding difficulties &/or FTT | Standard care w/gastroenterologist & nutritionist &/or speech therapist | Gastrostomy tube placement may be required for persistent feeding issues. |
| Strabismus/ Amblyopia | Standard care as per treating ophthalmologist | |
| Cardiac defects | Standard care as per treating cardiologist | |
| Seizures | Standard AEDs as recommended by an experienced neurologist. Consideration of brain MRI. | Many different AEDs may be effective; no single AED has been demonstrated effective specifically for this disorder. 1 |
AEDs= antiepileptic drugs; FTT = failure to thrive
- 1.
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.
Developmental Disability / 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 from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states and provides in-home services to target individual therapy needs.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center-based; however, for children too medically unstable to attend, home-based services are provided.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. Some issues to consider:
- Individualized education plan (IEP) services:
- An IEP provides specially designed instruction and related services to children who qualify
- IEP services will be reviewed annually to determine if any changes are needed.
- As required by special education law, children should be in the least restrict environment at school and included in general education as much as possible and when appropriate.
- Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
- PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
- A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
- 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 and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
- Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, 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. Assuming that the individual is safe to eat by mouth, feeding therapy – typically from an occupational or speech therapist – is recommended for affected individuals who have difficulty feeding due to poor oral motor control.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices to not hinder verbal development of speech and in many cases can improve it.
Social/Behavioral Difficulties
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 (ADHD), when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Surveillance
Table 5.
Recommended Surveillance for Individuals with WDR26-Related Intellectual Disability
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Constitutional | Eval of growth | Annually or more frequently if FTT |
| Eyes | Ophthalmologic eval | Annually or more frequently as needed |
| ENT/Mouth | ENT eval | As needed |
| Gastrointestinal/ Feeding | Assessment for constipation, gastroesophageal reflux, nutritional status, & feeding w/attention to poor weight gain, choking/gagging during feeds, & feeding refusal not otherwise explained | |
| Musculoskeletal | Physical therapy follow up for gait abnormality | |
| Neurologic | Follow up of seizure management | |
| Development | Monitor developmental progress & educational needs. | |
| Psychiatric/ Behavorial | Developmental psychologist eval | |
| Miscellaneous/ Other | Assess family need for social work support, other local resources. |
FTT = failure to thrive
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.