CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity

Michelle E Ernst^{1

2}, Evan H Baugh¹, Amanda Thomas³, Louise Bier¹, Natalie Lippa¹, Nicholas Stong¹, Maureen S Mulhern¹, Sulagna Kushary¹, Cigdem I Akman⁴, Erin L Heinzen^{1

5}, Raymond Yeh³, Weimin Bi⁶, Neil A Hanchard⁶, Lindsay C Burrage⁶, Magalie S Leduc⁶, Josephine S C Chong⁷, Renee Bend⁸, Michael J Lyons⁸, Jennifer A Lee⁸, Pim Suwannarat⁹, Eva Brilstra¹⁰, Marleen Simon¹⁰, Marije Koopmans¹⁰, Ellen van Binsbergen¹⁰, Daniel Groepper¹¹, Julie Fleischer¹¹, Caroline Nava¹², Boris Keren¹², Cyril Mignot^{12

13}, Sophie Mathieu¹⁴, Grazia M S Mancini¹⁵, Suneeta Madan-Khetarpal¹⁶, Elena M Infante¹⁶, Judith Bluvstein¹⁷, Andrea Seeley¹⁸, Kristine Bachman¹⁸, Eric W Klee^{19

20}, Laura E Schultz-Rogers^{19

20}, Linda Hasadsri²¹, Sarah Barnett²¹, Marissa S Ellingson²¹, Matthew J Ferber²², Vinodh Narayanan²³, Keri Ramsey²³, Anita Rauch²⁴, Pascal Joset²⁴, Katharina Steindl²⁴, Theodore Sheehan²⁵, Annapurna Poduri²⁵, Alejandra Vasquez^{25

26}, Claudia Ruivenkamp²⁷, Susan M White^{28

29}, Lynn Pais³⁰, Kristin G Monaghan³¹, David B Goldstein¹, Tristan T Sands^{1

4}, Vimla Aggarwal^{1

3}

Affiliations

¹ Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
² Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA.
³ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
⁴ Department of Neurology, The Neurological Institute of New York, Columbia University Irving Medical Center, New York, NY, USA.
⁵ Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁷ Joint CUHK-Baylor Center of Medical Genetics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁸ Greenwood Genetic Center, Greenwood, SC, USA.
⁹ Mid-Atlantic Permanente Medical Group, Rockville, MD, USA.
¹⁰ Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
¹¹ Department of Pediatrics, Southern Illinois University School of Medicine, Springfield, IL, USA.
¹² Department of Genetics, APHP Sorbonne University, Paris, France.
¹³ Reference Center for Intellectual Disabilities of Rare Causes, Paris, France.
¹⁴ Department of Neuropediatrics, APHP Sorbonne University, Trousseau Hospital, Paris, France.
¹⁵ Department of Clinical Genetics, ErasmusMC University Medical Center, Rotterdam, The Netherlands.
¹⁶ Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
¹⁷ School of Medicine, New York University, New York, NY, USA.
¹⁸ Geisinger Medical Center, Danville, PA, USA.
¹⁹ Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
²⁰ Department of Health Sciences, Mayo Clinic, Rochester, MN, USA.
²¹ Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
²² Clinical Genome Sequencing Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
²³ Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ, USA.
²⁴ Institute of Medical Genetics, University of Zürich, Schlieren, Zürich, Switzerland.
²⁵ Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
²⁶ Division of Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, USA.
²⁷ Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
²⁸ Victorian Clinical Genetics Service, Murdoch Children's Research Institute, Melbourne, Australia.
²⁹ Department of Paediatrics, University of Melbourne, Melbourne, Australia.
³⁰ Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³¹ GeneDx, Gaithersburg, MD, USA.

PMID: 34041744
PMCID: PMC9189716
DOI: 10.1111/epi.16931

CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity

Michelle E Ernst et al. Epilepsia. 2021 Jul.

. 2021 Jul;62(7):e103-e109.

doi: 10.1111/epi.16931. Epub 2021 May 26.

Authors

Affiliations

¹ Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
² Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA.
³ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
⁴ Department of Neurology, The Neurological Institute of New York, Columbia University Irving Medical Center, New York, NY, USA.
⁵ Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁷ Joint CUHK-Baylor Center of Medical Genetics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁸ Greenwood Genetic Center, Greenwood, SC, USA.
⁹ Mid-Atlantic Permanente Medical Group, Rockville, MD, USA.
¹⁰ Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
¹¹ Department of Pediatrics, Southern Illinois University School of Medicine, Springfield, IL, USA.
¹² Department of Genetics, APHP Sorbonne University, Paris, France.
¹³ Reference Center for Intellectual Disabilities of Rare Causes, Paris, France.
¹⁴ Department of Neuropediatrics, APHP Sorbonne University, Trousseau Hospital, Paris, France.
¹⁵ Department of Clinical Genetics, ErasmusMC University Medical Center, Rotterdam, The Netherlands.
¹⁶ Department of Medical Genetics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
¹⁷ School of Medicine, New York University, New York, NY, USA.
¹⁸ Geisinger Medical Center, Danville, PA, USA.
¹⁹ Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
²⁰ Department of Health Sciences, Mayo Clinic, Rochester, MN, USA.
²¹ Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
²² Clinical Genome Sequencing Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
²³ Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ, USA.
²⁴ Institute of Medical Genetics, University of Zürich, Schlieren, Zürich, Switzerland.
²⁵ Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
²⁶ Division of Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, USA.
²⁷ Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
²⁸ Victorian Clinical Genetics Service, Murdoch Children's Research Institute, Melbourne, Australia.
²⁹ Department of Paediatrics, University of Melbourne, Melbourne, Australia.
³⁰ Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³¹ GeneDx, Gaithersburg, MD, USA.

PMID: 34041744
PMCID: PMC9189716
DOI: 10.1111/epi.16931

Abstract

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.

Keywords: CSNK2A1; CK2; MSNE; casein kinase II; generalized epilepsy; myoclonic seizures; myoclonic status epilepticus.

PubMed Disclaimer

Figures

**Figure 1.**
*CSNK2B* genotypes and phenotypes. a) Mutational landscape of *CSNK2B*; boxes = functional domains; bar = autophosphorylation site; all 34 reported variants are shown (bold = recurrent variants; # = previously reported). Note p.Glu5Ter and p.Arg86Cys were reported in the same individual in Li *et al.* b) Neurodevelopmental phenotypes across all reported *CSNK2B* patients (n = 39), males (n = 25), females (n = 14); blue = no delays to date, yellow = mild or not otherwise specified, red = moderate to profound. c) Age of onset for all reported *CSNK2B* patients with epilepsy plotted as a cumulative frequency (n = 32).

See this image and copyright information in PMC

References

1. Gietz RD, Graham KC, Litchfield DW. Interactions between the subunits of casein kinase II. J Biol Chem. 1995;270(22):13017–21. - PubMed
1. St-Denis NA, Litchfield DW. Protein kinase CK2 in health and disease: From birth to death: the role of protein kinase CK2 in the regulation of cell proliferation and survival. Cell Mol Life Sci. 2009;66(11–12):1817–29. - PMC - PubMed
1. Ceglia I, Flajolet M, Rebholz H. Predominance of CK2alpha over CK2alpha’ in the mammalian brain. Mol Cell Biochem. 2011;356(1-2):169–75. - PubMed
1. Okur V, Cho MT, Henderson L, Retterer K, Schneider M, Sattler S, et al. De novo mutations in CSNK2A1 are associated with neurodevelopmental abnormalities and dysmorphic features. Hum Genet. 2016;135(7):699–705. - PubMed
1. Poirier K, Hubert L, Viot G, Rio M, Billuart P, Besmond C, et al. CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy. Hum Mutat. 2017;38(8):932–41. - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity

Affiliations

CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical