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. 2017 Aug 14;9(1):73.
doi: 10.1186/s13073-017-0463-8.

Phenotypic and Molecular Characterisation of CDK13-related Congenital Heart Defects, Dysmorphic Facial Features and Intellectual Developmental Disorders

Free PMC article

Phenotypic and Molecular Characterisation of CDK13-related Congenital Heart Defects, Dysmorphic Facial Features and Intellectual Developmental Disorders

Bret L Bostwick et al. Genome Med. .
Free PMC article


Background: De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder.

Methods: To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review.

Results: We demonstrate greater than expected phenotypic heterogeneity, including 33% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites.

Conclusions: Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified.

Keywords: Agenesis of the corpus callosum; CDK13; CHDFIDD; Cyclin-dependent kinase; De novo variant; Developmental delay; Hypertelorism; Neurodevelopmental disorders; Undiagnosed Diseases Network.

Conflict of interest statement

Ethics approval and consent to participate

The institutional review board of the Baylor College of Medicine approved this study. Participants were enrolled after written informed consent was obtained from parents or legal guardians. The study conforms to the Helsinki Declaration.

Consent for publication

Written informed consent for publication from the parents or legal guardians to publish the work was obtained.

Competing interests

Baylor College of Medicine (BCM) and Miraca Holdings Inc. have formed a joint venture with shared ownership and governance of the Baylor Genetics (BG), which performs clinical exome sequencing. JEP, MM, JAR, JRL, BL and SRL are employees of BCM and derive support through a professional services agreement with the BG. JRL serves on the Scientific Advisory Board of the BG. JRL has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen, Inc. and is a co-inventor of US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. The remaining authors declare that they have no competing interests.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Fig. 1
Fig. 1
a CDK13 Domain Composition. Proline-rich (PRM), alanine-rich (AR), Arginine/serine-rich (RS), and serine-rich (SR) domains are indicated. The protein kinase domains span amino acids 697–1029. Numbers below the schematic represent amino acid positions of various domains. Domain data adapted from [10]. b Summary of 29 total pathogenic variants including this report. All variants are predicted to impact the protein kinase domain with additional clustering in the ATP-binding and magnesium-binding sites. More than half (15/29) of the variants perturb the wild-type asparagine residue at amino acid position 842. Asterisk indicates variants contributed by this study: (1) variants published in [1]; (2) variants published in [2]. Variants present in more than one individual per publication are listed as ‘x #’
Fig. 2
Fig. 2
Craniofacial and dysmorphology features in individuals with pathogenic CDK13 variants. Patients share a facial gestalt which in some cases include hypertelorism, epicanthal folds, highly arched eyebrows, widened nasal bridge, short columella, thin upper lip and dysplastic ears. a Study ID 1001. b Study ID 1004. c Study ID 1006. d Study ID 1005. e Study ID 1002. f Study ID 1008. g Study ID 1007. h Study ID 1003
Fig. 3
Fig. 3
a Spectrum of ear abnormalities seen in individuals with CDK13 pathogenic variants. Ear abnormalities include over-folded superior helices, posterior angulation, low-set ears and cupping. b An unusual sacral bony prominence with an apical vertical slit identified in Individual 1001

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