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.

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 (or likely pathogenic) variant in WDR26 by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP 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 [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous WDR26 variant of uncertain significance does not establish or rule out the diagnosis.

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 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.

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. Affected individuals 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].

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.

Treatment of Manifestations

Surveillance

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

WDR26-related intellectual disability (ID) is inherited in an autosomal dominant manner and is typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• All probands reported to date with WDR26-related ID whose parents have undergone molecular genetic testing have the disorder as a result of a de novo WDR26 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the WDR26 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is that the proband inherited a pathogenic variant from a parent with germline mosaicism. Although theoretically possible, no instances of germline mosaicism have been reported to date.
• Theoretically, if the parent is the individual in whom the WDR26 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 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 [Rahbari et al 2016].

Offspring of a proband. Individuals with WDR26-related ID have not been known to reproduce; however, many are still children.

Other family members. Given that all probands with WDR26-related ID reported to date have the disorder as a result of a de novo WDR26 pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

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 parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Risk to future pregnancies is presumed to be low as the proband most likely has a de novo WDR26 pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. Given this risk, prenatal and preimplantation genetic testing may be considered.

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.

Molecular Pathogenesis

WDR26-related intellectual disability (ID) results from haploinsufficiency of WDR26 function [Skraban et al 2017]. However, little is known regarding how haploinsufficiency leads to specific cellular or developmental pathobiology that results in the human phenotype.

Gene structure. The WDR26 transcript NM_025160.6 has 14 exons, all of which contain coding sequence.

See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. The majority of WDR26 pathogenic variants have been de novo frameshift or nonsense variants. However, several missense variants have been noted in exons 4 and 5. All reported pathogenic variants to date are private to individual families.

The observation that core features of the 1q41q42 deletion syndrome consistently overlap those of WDR26-related ID strongly supports WDR26 haploinsufficiency as the basis of this deletion syndrome.

Normal gene product. The WDR26 protein includes 661 amino acids, and modeling suggests that it contains 14 variably perfect WD40 repeats. Together the 14 WD40 repeats compose two seven-bladed β propeller structures [Skraban et al 2017]:

• Domains WD1-WD7 (amino acids 1-353) comprise an N-terminal β propeller.
• Domains WD8-WD14 (amino acids 354-645) comprise a C-terminal β propeller, which includes the conserved LisH (LIS1 homology) and CTLH (C-terminal LIS homology) domains.

Although specific cellular functions for WDR26 are unclear, many WD40 repeat proteins play key roles in cellular scaffolding [Zhu et al 2004, Stirnimann et al 2010, Sun et al 2013].

Abnormal gene product. Most pathogenic WDR26 variants result in haploinsufficiency caused by either loss-of-function variants or deletion of part or all of the gene. However, several de novo missense pathogenic variants have been identified in the CTLH (aa 156-231) and WD6 (aa 254-304) domains that disrupt WDR26 protein [Skraban et al 2017].

Author Notes

Dr Skraban is a member of the faculty at the University of Pennsylvania Perelman School of Medicine and the Children's Hospital of Philadelphia. Dr Deardorff is a member of the faculty at the University of Southern California Keck School of Medicine and the Children's Hospital Los Angeles. They are working to further understand the clinical features and molecular pathogenesis associated with WDR26-related disorders with a goal to improve the lives of patients. They welcome both clinical and scientific inquiries, as well as individuals interested in their ongoing research registry (wdr26@email.chop.edu).

Acknowledgments

We would like to thank the families who have agreed to participate, as well as the many clinical colleagues who have referred patients and collaborated in these efforts.

Revision History

• 25 April 2019 (bp) Review posted live
• 10 May 2018 (cs) Original submission

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