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 anti-seizure medication.

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.

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 (or likely pathogenic) variant in CDK13 by molecular genetic testing (see Table 1).

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

Molecular genetic testing approaches can include a combination of 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).

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.

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].

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.

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 anti-seizure medication (ASM) by an experienced neurologist is indicated. No particular ASMs 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 Foundation Toolbox.

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

CDK13-related disorder is inherited in an autosomal dominant manner and is caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• All probands reported to date with CDK13 disorder whose parents have undergone molecular genetic testing have the disorder as a result of a de novo CDK13 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the CDK13 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.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the CDK13 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. To date, individuals with CDK13 disorder are not known to reproduce and fertility has not been assessed.

Other family members. Given that all probands with CDK13 disorder reported to date have the disorder as a result of a de novo CDK13 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 CDK13 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 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

CDK13 encodes a member of the cyclin-dependent serine/threonine protein kinase family. Members of this family serve an essential cellular role as master switches in cell cycle control. The exact function of cyclin-dependent kinase 13 (CDK13) has not yet been determined, but it may play a role in mRNA processing and may be involved in regulation of hematopoiesis [Chen et al 2007, Blazek et al 2011, Kohoutek & Blazek 2012, Chen et al 2014, Liang et al 2015, Zhang et al 2016].

Gene structure. The canonic CDK13 transcript variant (NM_003718.4) consists of 14 exons.

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

Pathogenic variants. All known pathogenic variants to date have occurred within the region encoding the protein kinase domain (spanning amino acids 697-998 of NP_003709.3). Within that domain there is additional clustering of variants within the ATP binding domain (amino acids 711-855) and the magnesium-binding site (at amino acid 842). In fact, approximately half of the pathogenic variants reported to date perturb the wild type asparagine residue at amino acid position 842 in the magnesium-binding site.

Pathogenic variants reported to date have included missense substitutions and splice site, frameshift, and nonsense variants [Bostwick et al 2017, Hamilton et al 2018, van den Akker et al 2018]. All reported variants to date are either proven or suspected to be de novo.

Normal gene product. The canonic transcript (NM_003718.4) encodes a 1,512-amino acid protein, containing a proline-rich domain, alanine-rich domain, arginine-serine-rich domain, and serine-rich domains.

Abnormal gene product. A variety of mechanisms have been proposed to date; additional functional studies are needed to further understand the pathogenic mechanism. Initially it was proposed that the absence of loss-of-function variants in the first 29 known individuals and the clustering of reported missense variants within a single protein domain make haploinsufficiency an unlikely mechanism [Bostwick et al 2017]. It was later suggested that CDK13 pathogenic variants act by a novel dominant-negative mechanism by potentially sequestering cyclin K into inactive complexes, thereby perturbing the function of the wild type protein [Hamilton et al 2018]. With the reporting of the first individuals with frameshift and nonsense variants, it was noted that the phenotypes were clinically indistinguishable from those with missense variants, favoring haploinsufficiency rather than a dominant-negative mechanism [van den Akker et al 2018].

Author Notes

Bret L Bostwick, MD is an assistant professor in the Department of Molecular and Human Genetics at Baylor College of Medicine in Houston, Texas. As a clinician and clinical researcher he has special interest in CDK13-related disorder and other neurodevelopmental disorders resulting from de novo pathogenic variants.

Acknowledgments

The author gratefully acknowledges the Undiagnosed Diseases Network (UDN) at Baylor College of Medicine Clinical Site for the diagnosis of the initial individual reported in Bostwick et al [2017].

Revision History

• 31 January 2019 (bp) Review posted live
• 29 January 2018 (bb) Original submission

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