Germline de novo variants in CSNK2B in Chinese patients with epilepsy

Abstract

CSNK2B, which encodes the beta subunit of casein kinase II (CK2), plays an important role in neuron morphology and synaptic transmission. Variants in CSNK2B associated with epilepsy and/or intellectual disability (ID)/developmental delay (DD) have been reported in five cases only. Among the 816 probands suspected hereditary epilepsy whose initial report of trio-based whole exome sequencing (WES) were negative, 10 de novo pathogenic or likely pathogenic variants of CSNK2B in nine probands were identified after reanalysis of their raw Trio-WES data. Six of the nine epileptic patients had ID/DD. The age of seizure onset of these nine patients with CSNK2B variants ranged from 2-12 months. Eight patients had age of seizure onset of less than 6 months. The epilepsy of most probands (8/9) was generalized tonic-clonic seizure and clustered (6/9). Most patients had normal electroencephalogram (5/9) and brain magnetic resonance image (7/9) results. Most patients (7/9) had easy-to-control seizures. Levetiracetam was the most commonly used drug in seizure-free patients (5/7). The variants detected in five patients (5/9, 55.6%) were located in the zinc-binding domain. In summary, our research provided evidence that variants in CSNK2B are associated with epilepsy with or without ID/DD. CSNK2B-related epilepsy is relatively easy to be controlled. The zinc-binding domain appears to be the hotspot region for mutation.

Figure 1

The Variants in CSNK2B DNA Sequence. CSNK2B has 648 nucleotides of coding sequence and contains seven exons. Square endings indicate that exons start or end after a complete codon, arrows to the right indicate that the last base of the last codon is located in the next exon, arrows to the left indicate that the last two bases are located in the exon. The variants in black fonts are from this study and the symbol * indicates that there are two cases with the variant. The variants highlighted in red are from recently reported patients with ID/DD and epilepsy^,, the variant highlighted in gold is from recently reported patient with ID, and the variants highlighted in green are from recently reported patient with profound ID and refractory epilepsy.

Figure 2

CLUSTAL O (1.2.4) multiple sequence alignment. The residues marked in color of CSNK2B is largely conserved across mammalian and other species. The symbol (*) under the sequences indicate identity. HUMAN, Homo sapiens (human); RAT, Rattus norvegicus (rat); MOUSE, Mus musculus (mouse); BOVIN, Bos taurus (bovine); RABIT, Oryctolagus cuniculus (rabbit); PIG, Sus scrofa (Pig); XENLA, Xenopus laevis (African clawed frog); HORSE, Equus caballus (horse); DNARE, Danio rerio (Zebrafish); CANLF, Canis lupus familiaris (dog); SHEEP, Ovis aries (sheep); CHICK, Gallus gallus (Chicken); FELCA, Felis catus (Cat).

Figure 3

EEGs of patients with CSNK2B variants (patient 1, 2 and 6). (A) Abnormal at the age of 3.5 years with diffuse spike-slow, multiple spike-slow, and slow wave discharging. Frequent myoclonic seizures were detected. (B) Abnormal at the age of 3 yrs. and 5 mos. with slow background and occasionally atypical spikes in the central area on the left. (C) Abnormal at the age of 6 mos. with frequent sharp waves in the frontal, central, middle temporal, and middle line regions during sleep synchronously or asynchronously.