Cdk13-Related Disorder
Summary
Clinical characteristics.
CDK13-related disorder, reported in 43 individuals to date, is characterized in all individuals by developmental delay / intellectual disability (DD/ID); nearly all individuals older than age one year display impaired verbal language skills (either absent or restricted speech). Other common findings are recognizable facial features in some individuals, behavioral problems (autism spectrum disorder or autistic traits/stereotypies, attention-deficit/hyperactivity disorder), feeding difficulties in infancy, structural cardiac defects, and seizures.
Diagnosis/testing.
The diagnosis of CDK13 disorder is established in a proband by identification of a heterozygous pathogenic variant in CDK13 by molecular genetic testing.
Management.
Treatment of manifestations: Management of DD/ID is per usual practice with attention to gross and fine motor skills, language and communication skills, and behavioral issues. Some children with feeding difficulties require tube feeding. Structural heart defects are treated in the usual manner by a cardiologist. Seizures are treated in the usual manner with antiepileptic drugs (AEDs).
Surveillance: For infants with feeding difficulties: Assess swallowing, feeding, nutritional status, and weight gain monthly during the first few months of life and then at least annually during childhood. Routine monitoring of developmental progress and educational needs. Annual assessment of behavior to identify new or evolving issues. As indicated by specialists: follow up of structural cardiac defects, seizures, scoliosis, constipation, and renal structural abnormalities.
Genetic counseling.
CDK13 disorder is inherited in an autosomal dominant manner. To date all probands whose parents have undergone molecular genetic testing have the disorder as a result of a de novo CDK13 pathogenic variant. Individuals with CDK13 disorder are not known to reproduce, and fertility has not been assessed. Given the estimated recurrence risk to sibs of 1% based on the theoretic possibility of parental germline mosaicism, prenatal testing and preimplantation genetic testing are options for parents of a child with CDK13 disorder.
Diagnosis
No formal clinical diagnostic criteria for CDK13 disorder have been published.
Suggestive Findings
CDK13 disorder should be considered in individuals with the following clinical and brain MRI findings.
Clinical findings
- Developmental delay / intellectual disability
- Structural cardiac defects
- Atrial septal defects
- Ventricular septal defects
- Pulmonary valve abnormalities
- Hypoplastic pulmonary artery
- Suggestive facial dysmorphisms (see Figure 1)
Figure 1.
Characteristic facial dysmorphisms in CDK13 disorder include hypertelorism or telecanthus; upslanting palpebral fissures; epicanthal folds; highly arched eyebrows; wide nasal bridge; short, broad columella; small mouth with thin upper lip; and abnormal (more...)
Brain MRI. Nonspecific findings in 15 individuals included the following:
- Agenesis/hypogenesis of the corpus callosum (5 individuals)
- Aplasia of the cerebellar vermis
- Periventricular leukomalacia or periventricular gliosis (3)
- Spinal cord syrinx (2)
- Cerebellar tonsillar abnormalities (2)
- Diminished white matter volume (1)
Establishing the Diagnosis
The diagnosis of CDK13 disorder is established in a proband by identification of a heterozygous pathogenic variant in CDK13 by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (typically exome sequencing).
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CDK13 disorder is nonspecific and indistinguishable from many other inherited disorders, it is most likely to be diagnosed by either a multigene panel (see Option 1) or genomic testing (see Option 2).
Option 1
A multigene panel that includes CDK13 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition 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. Of note, given the rarity of CDK13 disorder, some panels for congenital heart disease and/or ID 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.
Option 2
When the diagnosis of CDK13 disorder has not been considered, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
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 CDK13-Related Disorder
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| CDK13 | Sequence analysis 3 | 43/43 4 |
| Gene-targeted deletion/duplication analysis 5 | 0/43 |
- 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.
Sifrim et al [2016], Bostwick et al [2017], McRae et al [2017], Hamilton et al [2018], Uehara et al [2018], van den Akker et al [2018]
- 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.
Clinical Characteristics
Clinical Description
To date 43 individuals with CDK13 disorder have been reported [Sifrim et al 2016, Bostwick et al 2017, McRae et al 2017, Hamilton et al 2018, Uehara et al 2018, van den Akker et al 2018]. The features that occur commonly within the phenotypic spectrum of CDK13 disorder are discussed below; it is likely that our understanding of the phenotypic spectrum will evolve as additional affected individuals are identified.
The following are the most common clinical features of CDK13 disorder.
Seizures
Seizures have been reported in eight individuals with seizure types that include myoclonic, generalized tonic-clonic, and absence seizures. No correlation between the presence of structural brain abnormalities and seizure activity is apparent.
Gastrointestinal
The majority of infants with CDK13 disorder have a history of feeding difficulties including slow feeding and gastroesophageal reflux; seven eventually required gastrostomy tube feeding. Five infants had severe constipation, and one had anal stenosis.
Cardiac
The overall prevalence of structural cardiac defects is approximately 46% (17 of 37 evaluated for cardiac abnormality). Although structural heart defects were present in all seven of the initially reported individuals with CDK13 disorder, ascertainment was biased since these individuals were identified in a cohort with congenital heart disease. In contrast, four subsequent studies identified individuals with CDK13 disorder without structural cardiac defects [Bostwick et al 2017, Hamilton et al 2018, Uehara et al 2018, van den Akker et al 2018].
A variety of cardiac defects have been reported in the 17 with known cardiac defects; the most common, seen alone or in combination, are atrial septal defect (in 10 individuals) and ventricular septal defect (in 5).
Hypoplastic pulmonary arteries, dilated pulmonary arteries, and/or pulmonary valve abnormalities were reported in six individuals. Ebstein's anomaly and tetralogy of Fallot have also been reported.
One of the oldest individuals reported to date had bicuspid aortic valve, aortic stenosis, and aortic insufficiency diagnosed in childhood; when last evaluated at age 38 years cardiac findings included left ventricular non-compaction and sick sinus syndrome requiring pacemaker implantation [Bostwick et al 2017]. While the cardiomyopathy and electrical disturbance in this individual could indicate age-related penetrance of additional cardiac sequelae, to date long-term follow-up information of heart defects is limited to this one individual. The cardiac status of the male age 54 years reported by van den Akker et al [2018] is unknown.
Other
Growth. Birth weight, length, and head circumference appear to be within the normal range.
Short stature in childhood is present in about half of affected individuals. Endocrinologic evaluations of short stature have not been performed.
Microcephaly is more common in older individuals and, thus, may be acquired. Macrocephaly has been reported in three individuals to date [van den Akker et al 2018].
Eyes. Strabismus was reported in more than half of individuals evaluated (17/31). Other eye anomalies appear rare.
Renal anomalies reported to date include duplicated collecting systems, dilated collecting systems, and fused renal ectopia. The prevalence of renal abnormalities is unknown given the limited reports of renal imaging in published cases.
Spinal abnormalities included the following:
- Scoliosis in the absence of known vertebral abnormalities, hyperlordosis
- Vertebral hemangiomas
- Cervical spinal fusions
- Sacral clefting
- Spina bifida
- Sacral bony prominence
Musculoskeletal joint contractures, present in 2/16, are presumed secondary to spasticity. Contractures of the neck extensors and spinal extensors that limit flexion of the neck and spine were most prominent and contributed to atypical hyperextended posturing that appeared during the first year of life coinciding with the onset of spasticity.
Contractures at the Achilles tendons and knees were less severe.
Abnormalities of tone ranged from diffuse hypotonia to axial spasticity resulting in hyperextended posturing. In one series hypotonia was present in 11/16 and spasticity in 2/16 [Bostwick et al 2017]. Both children with spasticity had severe hypotonia at birth that evolved during the first year of life into spasticity (axial > appendicular).
Dental abnormalities. Wide-spaced peg-shaped teeth were reported in four individuals.
Hair. One third of individuals have curly hair.
Craniosynostosis has been reported to date in three individuals, at least one of whom required surgery for lambdoid and bicoronal synostosis.
Genotype-Phenotype Correlations
The small number of published cases to date limits the statistical power for evaluating genotype-phenotype correlations.
A possible genotype-phenotype correlation is the observation that the greater the decrease in total kinase activity the more severe the phenotype [Hamilton et al 2018].
- Variants affecting the lysine residue at position 734 (p.Lys734Arg and p.Lys734Glu) are predicted to exhibit a total loss of kinase activity by analogy with other kinases, but are also thought to have little or no effect on global protein stability or the ability to bind cyclin K [Hamilton et al 2018]. Thus, this variant is thought to exhibit a stronger dominant-negative effect. Indeed, the phenotypes of two individuals reported to date with this variant are on the more severe end of the spectrum and both also share growth restriction, microcephaly, and moderate-to-severe DD or ID [Bostwick et al 2017, Hamilton et al 2018].
- Variants affecting the asparagine residue at position 842 (p.Asn842Ser, p.Asn842Asp) are expected to cause total loss of kinase activity due to loss of ATP binding. In one series, individuals with these variants also showed a more severe phenotype than those with other pathogenic variants [Hamilton et al 2018], a finding not observed in another study [Bostwick et al 2017].
Two individuals harboring a stop codon at the end of the kinase domain may have shown a milder phenotype [van den Akker et al 2018]. It was also noted that the three unrelated individuals with frameshift variants and the two individuals with nonsense variants located at the C-terminal end of the kinase domain were clinically indistinguishable from those with missense variants, suggesting both haploinsufficiency and dominant-negative effect as mechanisms and limiting genotype-phenotype correlations.
Penetrance
Penetrance based on 43 individuals reported to date appears to be complete: all reported variants have been de novo and no unaffected individuals with a CDK13 pathogenic variant have been reported.
Prevalence
Forty-three individuals with CDK13 disorder have been reported to date. The prevalence in the general population is unknown.
A de novo CDK13 variant was detected in ~1.8% (7/398) of individuals in a cohort of individuals with syndromic congenital heart disease of unknown cause [Sifrim et al 2016].
In another cohort (which included some individuals from the Sifrim et al [2016] study) with developmental delay of unknown cause, a de novo CDK13 variant was detected in ~0.3% (11/3158) [McRae et al 2017].
Differential Diagnosis
Table 2.
Disorders with Developmental Delay / Intellectual Disability and other Anomalies to Consider in the Differential Diagnosis of CDK13-Related Disorder
| Disorder | Gene(s) | MOI | Clinical Features | |
|---|---|---|---|---|
| Overlapping | Distinguishing | |||
| KAT6B-related disorders | KAT6B | AD |
| In KAT6B-disorders:
|
| Kabuki syndrome | KDM6A KMT2D | XL AD |
| In Kabuki syndrome:
|
| Mowat-Wilson syndrome | ZEB2 | AD |
| In Mowat-Wilson syndrome:
|
AD = autosomal dominant; MOI = mode of inheritance; XL = X-linked
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CDK13 disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.
Table 3.
Recommended Evaluations for CDK13 Disorder Following Initial Diagnosis
| System/Concern | Evaluation | Comment |
|---|---|---|
| Constitutional | Assessment of height & weight for failure to thrive | |
| Eyes | Ophthalmologic eval for strabismus, nystagmus, &/or refractive error | |
| ENT/Mouth | Baseline dental eval for wide-spaced peg-shaped teeth | Referral to orthodontist if significant dental abnormalities |
| Cardiovascular | Baseline echocardiogram for structural cardiac anomalies | |
| Gastrointestinal/ Feeding |
|
|
| Genitourinary | Renal ultrasound | To assess for renal structural abnormalities |
| Musculoskeletal | Spinal imaging to evaluate for scoliosis, lordosis, cervical vertebral fusions, & sacral abnormalities | |
| Physical exam to evaluate for joint contractures | ||
| Eval for abnormal head shape | If present, consider imaging studies to evaluate for craniosynostosis. | |
| Neurologic | Neurologic eval |
|
| Psychiatric/ Behavioral | Neuropsychiatric eval | Screen persons age >12 mos for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD. |
| Miscellaneous/ Other | Developmental assessment | To incl motor, speech/language eval, general cognitive, & vocational skills |
| Consultation w/clinical geneticist &/or genetic counselor |
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
Treatment of Manifestations
Dental. Refer to an orthodontist for wide-spaced or peg-shaped teeth beginning at age two years.
Cardiovascular. Refer to a cardiologist or cardiothoracic surgeon for treatment of structural heart defects.
Gastrointestinal. Refer to a gastroenterologist for evaluation and treatment when chronic constipation is present.
Musculoskeletal
- Spinal abnormalities. Refer to an orthopedist for consideration of surgical treatment or bracing of scoliosis, and further evaluation of vertebral hemangiomas or spinal fusions.
- Contractures. Physical therapy, including stretching of the limbs and spine, can prevent contracture development. Splints, braces, or surgical release can help treat spinal or limb contractures.
- Craniosynostosis. Refer to a multidisciplinary craniofacial clinic (preferably one affiliated with a pediatric academic medical center) where staged surgical procedures can be tailored to individual needs as indicated. Initial surgeries can occur as early as age three to six months.
Neurologic
- Standardized treatment with antiepileptic drugs (AEDs) by an experienced neurologist is indicated. No particular AEDs have shown increased efficacy in CDK13 disorder [Author, personal observation].
- 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 Delay / 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. In the US, early intervention is a federally funded program available in all states.
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.
Ages 5-21 years
- In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
- Discussion about transition plans including financial, vocation/employment if feasible, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
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.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
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.
- Consider use of durable medical equipment 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.
Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of ASD, 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 ADHD, when necessary.
Surveillance
Table 4.
Recommended Surveillance for Individuals with CDK13-Related Disorder
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Eyes | Ophthalmologic eval | Annually during childhood to monitor for strabismus or refractive errors |
| ENT/Mouth | Routine dental/orthodontics | As indicated if dental anomalies are present |
| Cardiovascular |
| As indicated if structural cardiac disease is present |
| Gastrointestinal/ Feeding | For those w/feeding difficulties: assessment of swallowing, feeding, nutritional status, weight gain | Monthly in 1st few mos of life, then at least yearly during childhood |
| Constipation | As indicated if chronic constipation is present | |
| Renal | For those w/renal structural abnormalities | Annual laboratory eval for renal function as indicated |
| Musculoskeletal | For those w/spinal abnormalities | Annual monitoring for scoliosis progression |
| For those w/joint contractures | Annual monitoring of joints for restriction in range of motion | |
| Neurologic | Monitor treatment effectiveness in those w/seizures. | As indicated if clinical seizure activity is suspected |
| Psychiatric/ Behavioral | Behavioral assessment | Annual assessment |
| Miscellaneous/ Other | Monitor developmental progress & educational needs. | Annual assessment |
| Clinical genetics eval | Annually to update family of any new medical recommendations or changes to recommended mgmt |
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.