Key result
Among 30 patients with novel KCNQ2 variants, those with single-nucleotide variants exhibited variable phenotypes including neurodevelopmental delay, whereas those with 20q13.3 deletions generally had normal neurological development.
Why the study?
The relationship between genotype and phenotype in KCNQ2-related disorders remains elusive.
Observational (n=30)
Yes
Patients with novel KCNQ2 variants exhibit variable phenotypes, with seizures being the dominant initial feature, while those with 20q13.3 deletions tend to have normal neurological development.
Answers are grounded in this paper and cite their sources.
Novel KCNQ2 variants may refine neonatal seizure prognosis; hypothesis-generating for genotype-phenotype links pending validation.
Background KCNQ2-related disorder is typically characterized as neonatal onset seizure and epileptic encephalopathy. The relationship between its phenotype and genotype is still elusive. This study aims to provide clinical features, management, and prognosis of patients with novel candidate variants of the KCNQ2 gene. Methods We enrolled patients with novel variants in the KCNQ2 gene from the China Neonatal Genomes Project between January 2018 and January 2021. All patients underwent next-generation sequencing tests and genetic data were analyzed by an in-house pipeline. The pathogenicity of variants was classified according to the guideline of the American College of Medical Genetics. Each case was evaluated by two geneticists back to back. Patients' information was acquired from clinical records. Results A total of 30 unrelated patients with novel variants in the KCNQ2 gene were identified, including 19 patients with single-nucleotide variants (SNVs) and 11 patients with copy number variants (CNVs). For the 19 SNVs, 12 missense variants and 7 truncating variants were identified. Of them, 36.8% (7/19) of the KCNQ2 variants were located in C-terminal regions, 15.7% (3/19) in segment S2, and 15.7% (3/19) in segment S4. Among them, 18 of 19 patients experienced seizures in the early neonatal period. However, one patient presented neurodevelopmental delay (NDD) as initial phenotype when he was 2 months old, and he had severe NDD when he was 3 years old. This patient did not present seizure but had abnormal electrographic background activity and brain imaging. Moreover, for the 11 patients with CNVs, 20q13.3 deletions involving EEF1A2, KCNQ2, and CHRNA4 genes were detected. All of them presented neonatal-onset seizures, responded to antiepileptic drugs, and had normal neurological development. Conclusion In this study, patients with novel KCNQ2 variants have variable phenotypes, whereas patients with 20q13.3 deletion involving EEF1A2, KCNQ2, and CHRNA4 genes tend to have normal neurological development.
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Xiao et al. (2022) conducted an observational in KCNQ2-related disorders (n=30). Novel KCNQ2 variants and deletions was evaluated on Clinical phenotypes and neurological development. Among 30 patients with novel KCNQ2 variants, those with single-nucleotide variants exhibited variable phenotypes including neurodevelopmental delay, whereas those with 20q13.3 deletions generally had normal neurological development.
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