CNKSR2-related neurodevelopmental and epilepsy disorder: a cohort of 13 new families and literature review indicating a predominance of loss of function pathogenic variants

BMC Medical Genomics

Christopher Wardley¹  Jennifer Wardley¹  Susan Singh²  Leigh Ann Higa³  Joseph J. Shen⁴  Timothy Foster⁵ 

[1]CNKSR2 Family Support Group, Rochdale, Lancashire, UK

[2]CNKSR2 Family Support Group, Sanger, CA, USA

[3]Department of Pediatrics, Community Regional Medical Center, Fresno, CA, USA

[4]Division of Genomic Medicine, Department of Pediatrics, MIND Institute, University of California, Davis, 2825 50th Street, 95817, Sacramento, CA, USA

[5]Division of Genetics, Department of Pediatrics, UCSF Fresno, Fresno, CA, USA

[6]Division of Genomic Medicine, Department of Pediatrics, MIND Institute, University of California, Davis, 2825 50th Street, 95817, Sacramento, CA, USA

[7]Division of Pediatric Neurology, Department of Pediatrics, UCSF Fresno, Fresno, CA, USA

关键词: CNKSR2;    CNK2;    Epilepsy;    ESES;    CSWS;    Developmental delay;   

DOI  :  10.1186/s12920-021-01033-7

来源: Springer

【 摘 要 】

BackgroundPathogenic variants in connector enhancer of kinase suppressor of Ras-2 (CNKSR2) located on the X chromosome (Xp22.12) lead to a disorder characterized by developmental delay and a characteristic seizure phenotype. To date, 20 affected males representing 13 different pathogenic variants have been published.Case presentationWe identified an 8-year-old male with seizures, abnormal electroencephalogram (EEG) with epileptiform abnormalities in the right hemisphere, and developmental delay with notable loss of speech following seizure onset. Additional concerns include multiple nighttime awakenings, hyperactivity, and autism spectrum disorder. Genetic testing identified a de novo pathogenic nonsense variant in CNKSR2.Through an active family support group, an additional 12 males are described, each harboring a different CNKSR2 variant. The clinical presentation and natural history consistently show early developmental delay, sleep disturbances, and seizure onset in childhood that is initially intractable but later becomes better controlled. Virtually all of the pathogenic variants are predicted to be loss of function, including genomic deletions, nonsense variants, splice site mutations, and small insertions or deletions.ConclusionsThis expanded knowledge, combined with functional studies and work with animal models currently underway, will enable a better understanding and improved ability to care for individuals with CNKSR2-related neurodevelopmental and epilepsy disorder.

【 授权许可】

CC BY