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Identification of CNKSR2 Pathogenic Variant and Detection of Strong X-chromosome Inactivation in a Female with Severe DEE-SWAS

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
CNKSR2 is a crucial regulator of RAC1, which plays a significant role in the growth of neuronal dendrites. Heterozygous pathogenic variants of CNKSR2 are associated with intellectual disability with epilepsy, including Developmental and epileptic encephalopathy with spike-wave activation in sleep (DEE-SWAS). However, due to its X-linked recessive genetic disorder, girls are typically asymptomatic. In this study, we identified a pathogenic variant in CNKSR2 in a girl with intractable epilepsy and also demonstrate that there was a strong skewing of X-chromosome-inactivation (XCI). This made it possible to make a definitive diagnosis and provide appropriate treatment. We also present a case of a boy with a novel pathogenic variant in CNKSR2 and report on it with a literature review.

Case Presentation
Case 1:

A 7-year-old girl developed afebrile generalized tonic-clonic seizures at the age of 2. Brain MRI revealed no abnormalities, and electroencephalogram (EEG) showed spikes and waves with a left centrotemporal dominance. Despite treatment with multiple antiepileptic drugs such as Levetiracetam, Sodium valproate, and Lamotrigine (LTG), her epileptic seizures remained intractable, and she repeatedly experienced status epilepticus several times a month. Although the frequency of status epilepticus decreased with Clobazam, developmental delays with regression became prominent during the course (Developmental Quotient:40). Additionally, her unsteady gait worsened, and the EEG findings also deteriorated, so we performed genetic testing.

Case 2:

An 11-year-old boy presented with a history of febrile convulsions at the age of 1 and epilepsy at the age of 3, and his condition was intractable. He never spoke meaningful words and exhibited severe developmental delays. Because he had symptoms like Angelman syndrome, including a distinctive facial appearance and ataxic gait, we performed Fluorescence in situ hybridization (FISH) and DNA methylation analysis, but no abnormalities were found. To confirm the diagnosis, genetic testing was performed.

 

Diagnostic Workup
With the consent of the families, whole genome sequencing was conducted on both cases as a trio consisting of the affected child and their parents. After confirming the results, in case 1, we performed an analysis of XCI using the methylation-sensitive enzyme (Hpa2) with her white blood cell DNA.

Treatment and Management
In Case 1, a CNKSR2 c.2134C>T, p.(Arg712Ter) heterozygous variant (de novo, previously reported) was found. There was a significant skewing of 85 : 15 in the X chromosome inactivation analysis using Hpa2. LTG was discontinued and Ethosuximide and Sulthiame, which have been reported effective in DEE-SWAS, were started.

Outcome and Follow-Up
In Case 1, the number of words spoken increased along with a decrease in the frequency of unsteadiness and seizures decreased. In case 2, a hemizygous variant (maternal, novel) of c.492C>A, p.(Cys164Ter) in CNKSR2 was identified. As the patient was a boy, a definitive diagnosis was made.

 

Discussion
There have been reports of neurological symptoms caused by a skewing of XCI in females with heterozygous pathogenic variants in CNKSR2. However, this case was more severe than the previously reported female cases, and the skewing of XCI was more pronounced. There is a strong possibility that the severity of this condition in women is correlates with the skewing of XCI.

Conclusion
To ensure appropriate diagnosis and treatment for cases of intractable epilepsy in girls, it may be necessary to analyze the XCI pattern.

Agenda

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