Clinical Study of 30 Novel KCNQ2 Variants/Deletions in KCNQ2-Related Disorders

Abstract

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.

Keywords: KCNQ2; Kv7.2; epilepsy; epileptic encephalopathy; newborn.

Figure 1

The distribution of the 19 novel variations in the KCNQ2 gene. (A) Approximate locations of the 19 novel KCNQ2 variants. KCNQ2 protein has six transmembrane domains (blue). The fourth segment acts as the voltage sensor, and the loop between the fifth and sixth domains forms the ion pore in the Kv7.2 potassium channel. (B) The distribution of exons and protein domain in the KCNQ2 gene. The wide box represents the coding region in the 17 exons. S1: segment S1, S2: segment S2, S3: segment S3, S4: segment S4, S5: segment S5, S6: segment S6, S3_S4_extracelluar: the extracellular region between segment S3 and segment S4; S4_S5_cytoplasmic: the cytoplasmic region between segment S4 and segment S5; pore_loop: the loop between the fifth and sixth domains forms the ion pore in a K7.2 potassium channel.