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Genome Med. 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.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA. bostwick@bcm.edu.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.
3
Department of Pediatrics, Baylor College of Medicine, San Antonio, TX, 78207, USA.
4
Division of Medical Genetics, A.I. duPont Hospital for Children/Nemours, Wilmington, DE, USA.
5
Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA, USA.
6
Baylor Genetics, Baylor College of Medicine, Houston, TX, USA.
7
Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
8
Department of Pediatrics, Section of Medical Genetics, West Virginia University Health Sciences Center, Morgantown, WV, USA.
9
Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA, USA.
10
Division of Magnetic Resonance Imaging, Silesian Center for Heart Disease, Zabrze, Poland.
11
The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
12
Texas Children's Hospital, Houston, TX, 77030, USA.
13
Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
14
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.

Abstract

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

PMID:
28807008
PMCID:
PMC5557075
DOI:
10.1186/s13073-017-0463-8
[Indexed for MEDLINE]
Free PMC Article

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