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Tytuł:
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Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders.
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Autorzy:
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Bostwick BL; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA. .
McLean S; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.; Department of Pediatrics, Baylor College of Medicine, San Antonio, TX, 78207, USA.
Posey JE; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.
Streff HE; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.
Gripp KW; Division of Medical Genetics, A.I. duPont Hospital for Children/Nemours, Wilmington, DE, USA.
Blesson A; Division of Medical Genetics, A.I. duPont Hospital for Children/Nemours, Wilmington, DE, USA.
Powell-Hamilton N; Division of Medical Genetics, A.I. duPont Hospital for Children/Nemours, Wilmington, DE, USA.
Tusi J; Division of Medical Genetics, A.I. duPont Hospital for Children/Nemours, Wilmington, DE, USA.
Stevenson DA; Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Farrelly E; Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Hudgins L; Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Yang Y; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.; Baylor Genetics, Baylor College of Medicine, Houston, TX, USA.
Xia F; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.; Baylor Genetics, Baylor College of Medicine, Houston, TX, USA.
Wang X; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.; Baylor Genetics, Baylor College of Medicine, Houston, TX, USA.
Liu P; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.; Baylor Genetics, Baylor College of Medicine, Houston, TX, USA.
Walkiewicz M; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.; Baylor Genetics, Baylor College of Medicine, Houston, TX, USA.
McGuire M; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.
Grange DK; Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
Andrews MV; Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
Hummel M; Department of Pediatrics, Section of Medical Genetics, West Virginia University Health Sciences Center, Morgantown, WV, USA.
Madan-Khetarpal S; Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA, USA.
Infante E; Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA, USA.
Coban-Akdemir Z; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.
Miszalski-Jamka K; Division of Magnetic Resonance Imaging, Silesian Center for Heart Disease, Zabrze, Poland.
Jefferies JL; The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.
Emrick L; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.
Nugent KM; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.; Department of Pediatrics, Baylor College of Medicine, San Antonio, TX, 78207, USA.
Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.; Texas Children's Hospital, Houston, TX, 77030, USA.; Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
Belmont JW; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.
Lee B; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.
Lalani SR; Department of Molecular and Human Genetics, Baylor College of Medicine, 6701 Fannin St, Suite 1560, Houston, TX, 77030, USA.
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Corporate Authors:
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Members of the Undiagnosed Diseases Network
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Źródło:
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Genome medicine [Genome Med] 2017 Aug 14; Vol. 9 (1), pp. 73. Date of Electronic Publication: 2017 Aug 14.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
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Język:
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English
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Imprint Name(s):
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Original Publication: [London] : BioMed Central
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MeSH Terms:
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Mutation*
Phenotype*
CDC2 Protein Kinase/*genetics
Face/*abnormalities
Heart Defects, Congenital/*metabolism
Intellectual Disability/*metabolism
Adolescent ; Adult ; Child ; Child, Preschool ; Female ; Heart Defects, Congenital/genetics ; Humans ; Infant ; Intellectual Disability/genetics ; Male ; Syndrome
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References:
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Biochem Biophys Res Commun. 2000 Dec 29;279(3):832-7. (PMID: 11162436)
Exp Neurol. 2014 Nov;261:10-21. (PMID: 24999027)
Nature. 2017 Feb 23;542(7642):433-438. (PMID: 28135719)
Genes Dev. 2011 Oct 15;25(20):2158-72. (PMID: 22012619)
Genome Med. 2016 Jan 06;8(1):3. (PMID: 26739615)
Nat Genet. 2016 Sep;48(9):1060-5. (PMID: 27479907)
Nat Cell Biol. 2009 Nov;11(11):1275-6. (PMID: 19884882)
Mol Cell Biol. 2015 Mar;35(6):928-38. (PMID: 25561469)
BMC Evol Biol. 2014 Jan 17;14:10. (PMID: 24433236)
Cell Div. 2012 Apr 18;7:12. (PMID: 22512864)
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Grant Information:
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K08 HG008986 United States HG NHGRI NIH HHS; T32 GM007526 United States GM NIGMS NIH HHS; U01 HG007709 United States HG NHGRI NIH HHS; UM1 HG006542 United States HG NHGRI NIH HHS
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Contributed Indexing:
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Keywords: Agenesis of the corpus callosum; CDK13; CHDFIDD; Cyclin-dependent kinase; De novo variant; Developmental delay; Hypertelorism; Neurodevelopmental disorders; Undiagnosed Diseases Network
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Substance Nomenclature:
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EC 2.7.11.22 (CDC2 Protein Kinase)
EC 2.7.11.22 (CDK13 protein, human)
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Entry Date(s):
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Date Created: 20170816 Date Completed: 20170901 Latest Revision: 20230807
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Update Code:
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20240105
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PubMed Central ID:
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PMC5557075
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DOI:
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10.1186/s13073-017-0463-8
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PMID:
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28807008
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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.
