Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders

Members of the Undiagnosed Diseases Network

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Number of pages1
JournalGenome medicine
Volume9
Issue number1
DOIs
StatePublished - Aug 14 2017

Fingerprint

Exome
Congenital Heart Defects
Penetrance
Protein Kinases
Magnesium
Cluster Analysis
Heart Diseases
Adenosine Triphosphate
Binding Sites
Guidelines
Kidney
Research
Protein Domains

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders. / Members of the Undiagnosed Diseases Network.

In: Genome medicine, Vol. 9, No. 1, 14.08.2017.

Research output: Contribution to journalArticle

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title = "Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders",
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.",
author = "{Members of the Undiagnosed Diseases Network} and Bostwick, {Bret L.} and Scott McLean and Posey, {Jennifer E.} and Streff, {Haley E.} and Gripp, {Karen W.} and Alyssa Blesson and Nina Powell-Hamilton and Jessica Tusi and Stevenson, {David A.} and Ellyn Farrelly and Louanne Hudgins and Yaping Yang and Fan Xia and Xia Wang and Pengfei Liu and Magdalena Walkiewicz and Marianne McGuire and Grange, {Dorothy K.} and Andrews, {Marisa V.} and Marybeth Hummel and Suneeta Madan-Khetarpal and Elena Infante and Zeynep Coban-Akdemir and Karol Miszalski-Jamka and Jefferies, {John L.} and Rosenfeld, {Jill A.} and John Jefferies and Nugent, {Kimberly M.} and Lupski, {James R.} and Belmont, {John W.} and Brendan Lee and Lalani, {Seema R.}",
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AU - Members of the Undiagnosed Diseases Network

AU - Bostwick, Bret L.

AU - McLean, Scott

AU - Posey, Jennifer E.

AU - Streff, Haley E.

AU - Gripp, Karen W.

AU - Blesson, Alyssa

AU - Powell-Hamilton, Nina

AU - Tusi, Jessica

AU - Stevenson, David A.

AU - Farrelly, Ellyn

AU - Hudgins, Louanne

AU - Yang, Yaping

AU - Xia, Fan

AU - Wang, Xia

AU - Liu, Pengfei

AU - Walkiewicz, Magdalena

AU - McGuire, Marianne

AU - Grange, Dorothy K.

AU - Andrews, Marisa V.

AU - Hummel, Marybeth

AU - Madan-Khetarpal, Suneeta

AU - Infante, Elena

AU - Coban-Akdemir, Zeynep

AU - Miszalski-Jamka, Karol

AU - Jefferies, John L.

AU - Rosenfeld, Jill A.

AU - Jefferies, John

AU - Nugent, Kimberly M.

AU - Lupski, James R.

AU - Belmont, John W.

AU - Lee, Brendan

AU - Lalani, Seema R.

PY - 2017/8/14

Y1 - 2017/8/14

N2 - 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.

AB - 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.

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