NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

WDR26-Related Intellectual Disability

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

Author Information

Initial Posting: .

Estimated reading time: 17 minutes

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 diagnosis 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.

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 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
WDR26Sequence analysis 315/15 4
Gene-targeted deletion/duplication analysis 5Unknown; see footnote 6
Chromosomal microarray 7Unknown; see footnote 8
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.

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
MOIClinical Features of the Differential Diagnosis Disorder
Overlapping w/WDR26-related IDDistinguishing from WDR26-related ID
Angelman syndromeDeficient
expression/
function of
maternally
inherited UBE3A allele
See footnote 1
  • Happy demeanor
  • Seizures
  • Abnormal gait
  • Widely spaced teeth
  • Inappropriate laughter/excitability
  • Microcephaly common
Pitt-Hopkins syndromeTCF4 or
deletion of the
chromosome
region in which
TCF4 is located
See footnote 2
  • Seizures
  • Widely spaced teeth
  • Full lips
  • Episodic hyperventilation &/or breath-holding spells
  • Severe myopia
Alpha-thalassemia X-linked intellectual disability syndromeATRXXL
  • Hypotonia
  • Coarse facial features
  • Alpha-thalassemia & HbH inclusion bodies
  • Genital anomalies
  • Microcephaly common
  • Postnatal growth deficiency
Kleefstra syndromeEHMT1 or
deletion at
9q34.3
AD
  • Seizures
  • Hypotonia
  • Autistic features
  • Congenital malformations more common
  • Severe infections

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/ConcernEvaluationComment
ConstitutionalAssessment of height, weight, head circumferenceEvaluation of growth parameters to identify those w/FTT
NeurologicNeurologic evaluationIncl EEG & brain MRI if seizures
DevelopmentDevelopmental assessmentIncl assessment of age-appropriate motor, speech/language, cognitive skills.
EyesOphthalmologic evaluationFor evidence of refractive error, strabismus ± amblyopia, cataracts, abnormal extraocular movement
ENT/MouthConsultation w/ENTFor those w/:
  • Recurrent otitis media
  • Cleft palate
CardiovascularConsultation w/cardiologistIf evidence of congenital heart defect
RespiratoryConsultation w/pulmonologistIf evidence of tracheomalacia
Gastrointestinal/
Feeding
Gastroenterology / nutrition / feeding team evaluationFor those w/:
  • Feeding difficulties, GERD, &/or FTT: assess swallowing, feeding, & nutritional status to determine safety of oral vs gastrostomy feeding
  • Constipation
MusculoskeletalConsultation w/physiatristFor those w/gait abnormalities
Psychiatric/
Behavioral
Neuropsychiatric evaluationScreen 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
TreatmentConsiderations/Other
Feeding
difficulties
&/or FTT
Standard care w/gastroenterologist & nutritionist &/or speech therapistGastrostomy tube placement may be required for persistent feeding issues.
Strabismus/
Amblyopia
Standard care as per treating ophthalmologist
Cardiac defectsStandard care as per treating cardiologist
SeizuresStandard 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/ConcernEvaluationFrequency
ConstitutionalEvaluation of growthAnnually or more frequently if FTT
EyesOphthalmologic evaluationAnnually or more frequently as needed
ENT/MouthENT evaluationAs 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 explainedAs needed
MusculoskeletalPhysical therapy follow up for gait abnormalityAs needed
NeurologicFollow up of seizure managementAs needed
DevelopmentMonitor developmental progress & educational needs.As needed
Psychiatric/
Behavorial
Developmental psychologist evaluationAs needed
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.

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

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

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 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.

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

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 testing and preimplantation genetic diagnosis may be considered.

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
    Phone: 800-232-4636 (toll-free)
    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
  • The WDR26 Registry at the Children’s Hospital of Philadelphia
    Email: WDR26@email.chop.edu

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.

WDR26-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 WDR26-Related Intellectual Disability (View All in OMIM)

617424WD REPEAT-CONTAINING PROTEIN 26; WDR26
617616SKRABAN-DEARDORFF SYNDROME; SKDEAS

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].

References

Literature Cited

  • Au PY, Argiropoulos B, Parboosingh JS, Micheil Innes A. Refinement of the critical region of 1q41q42 microdeletion syndrome identifies FBXO28 as a candidate causative gene for intellectual disability and seizures. Am J Med Genet A. 2014;164A:441–8. [PubMed: 24357076]
  • Balak C, Belnap N, Ramsey K, Joss S, Devriendt K, Naymik M, Jepsen W, Siniard AL, Szelinger S, Parker ME, Richholt R, Izatt T, Lafleur M, Terraf P, Llaci L, De Both M, Piras IS, Rangasamy S, Schrauwen I, Craig DW, Huentelman M, Narayanan V. A novel FBXO28 frameshift mutation in a child with developmental delay, dysmorphic features, and intractable epilepsy: a second gene that may contribute to the 1q41-q42 deletion phenotype. Am J Med Genet A. 2018;176:1549–58. [PubMed: 30160831]
  • Cassina M, Rigon C, Casarin A, Vicenzi V, Salviati L, Clementi M. FBXO28 is a critical gene of the 1q41q42 microdeletion syndrome. Am J Med Genet A. 2015;167:1418–20. [PubMed: 25900767]
  • Filges I, Rothlisberger B, Boesch N, Weber P, Wenzel F, Huber AR, Heinimann K, Miny P. Interstitial deletion 1q42 in a patient with agenesis of corpus callosum: phenotype-genotype comparison to the 1q41q42 microdeletion suggests a contiguous 1q4 syndrome. Am J Med Genet. 2010;152A:987–93. [PubMed: 20358614]
  • Kantarci S, Ackerman KG, Russell MN, Longoni M, Sougnez C, Noonan KM, Hatchwell E, Zhang X, Vanmarcke RP, Anyane-Yeboa K, Dickerman P, Wilson J, Donahoe PK, Pober BR. Characterization of the chromosome 1q41q42.12 region, and the candidate gene DISP1, in patients with CDH. Am J Med Genet. 2010;152A:2493–504. [PMC free article: PMC3797530] [PubMed: 20799323]
  • Mazzeu JF, Krepischi-Santos AC, Rosenbery C, Szuhai K, Knijnenburg J, Weiss JMM, Kerkis I, Mustacchi Z, Colin G, Mombach R, Pavanello RCM, Otto PA, Vianna-Morgante AM. Chromosome abnormalities in two patients with features of autosomal dominant Robinow syndrome. Am J Med Genet. 2007;143A:1790–5. [PubMed: 17603805]
  • Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
  • Rice GM, Qi Z, Selzer R, Richmond T, Thompson K, Pauli RM, Yu J. Microdissection-based high resolution genomic array analysis of two patients with cytogenetically identical interstitial deletion of chromosome 1q but distinct clinical phenotypes. Am J Med Genet. 2006;140:1637–43. [PubMed: 16835927]
  • Rosenfeld JA, Lacassie Y, El-Khechen D, Escobar LF, Reggin J, Hueur C, Chen E, Jenkins LS, Collins AT, Zinner S, Babcock M, Morrow B, Schultz RA, Torchia BS, Ballif BC, Tsuchiya KD, Shaffer LG. New cases and refinement of the critical region in the 1q41q42 microdeletion syndrome. Eur J Med Genet. 2011;54:42–9. [PubMed: 20951845]
  • Shaffer LG, Theisen A, Bejjani BA, Ballif BC, Aylsworth AS, Lim C, Mcdonald M, Ellison JW, Kostiner D, Saitta S, Shaikh T. The discovery of microdeletion syndromes in the post-genomic era: review of the methodology and characterization of a new 1q41q42 microdeletion syndrome. Genet Med. 2007;9:607–16. [PubMed: 17873649]
  • Skraban CM, Wells CF, Markose P, Cho MT, Nesbitt AI, Au PYB, Begtrup A, Bernat JA, Bird LM, Cao K, de Brouwer APM, Denenberg EH, Douglas G, Gibson KM, Grand K, Goldenberg A, Innes AM, Juusola J, Kempers M, Kinning E, Markie DM, Owens MM, Payne K, Person R, Pfundt R, Stocco A, Turner CLS, Verbeek NE, Walsh LE, Warner TC, Wheeler PG, Wieczorek D, Wilkens AB, Zonneveld-Huijssoon E, Kleefstra T, Robertson SP, Santani A, van Gassen KLI, Deardorff MA, et al. WDR26 haploinsufficiency causes a recognizable syndrome of intellectual disability, seizures, abnormal gait, and distinctive facial features. Am J Hum Genet. 2017;101:139–48. [PMC free article: PMC5501873] [PubMed: 28686853]
  • Slavotinek AM, Moshrefi A, Lopenjimenez N, Chao R, Mendell A, Shaw GM, Pennacchio LA, Bates MD. Sequence variants in the HLX gene at chromosome 1q41-1q42 in patients with diaphragmatic hernia. Clin Genet. 2009;75:429–39. [PMC free article: PMC2874832] [PubMed: 19459883]
  • Stirnimann CU, Petsalaki E, Russell RB, Muller CW. WD40 proteins propel cellular networks. Trends Biochem Sci. 2010;35:565–74. [PubMed: 20451393]
  • Sun Z, Smrcka AV, Chen S. WDR26 functions as a scaffolding protein to promote Gbetagamma-mediated phospholipase C beta2 (PLCbeta2) activation in leukocytes. J Biol Chem. 2013;288:16715–25. [PMC free article: PMC3675605] [PubMed: 23625927]
  • Wat MJ, Veenma D, Hogue J, Holder AM, Yu Z, Wat J, Hanchard N, Shchelochkov OA, Fernandes CJ, Johnson A, Lally KP, Slavotinek A, Danhaive O, Schaible T, Cheung SW, Rauen KA, Tonk VS, Tibboel D, De Klein A, Scott DA. Genomic alterations that contribute to the development of isolated and non-isolated congenital diaphragmatic hernia. J Med Genet. 2011;48:299–307. [PMC free article: PMC3227222] [PubMed: 21525063]
  • Yanagishita T, Yamamoto-Shimojima K, Nakano S, Sasaki T, Shigematsu H, Imai K, Yamamoto T. Phenotypic features of 1q41q42 microdeletion including WDR26 and FBXO28 are clinically recognizable: the first case from Japan. Brain Dev. 2019;41:452–5. [PubMed: 30635136]
  • Zhu Y, Wang Y, Xia C, Li D, Li Y, Zeng W, Yuan W, Liu H, Zhu C, Wu X, Liu M. WDR26: a novel Gbeta-like protein, suppresses MAPK signaling pathway. J Cell Biochem. 2004;93:579–87. [PubMed: 15378603]

Chapter Notes

Author Notes

Drs Skraban and Deardorff are faculty at the University of Pennsylvania Perelman School of Medicine and the Children's Hospital of Philadelphia. 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
Copyright © 1993-2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2020 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK540448PMID: 31021590

Views

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...