Figure 1: Electroencephalogram showing generalized epileptiform spike–wave discharges with markedly disorganized, high-amplitude background activity, indicative of a severe developmental and epileptic encephalopathy.

The identified variant in the KCNT2 gene (ENST00000294725.14) was a heterozygous nonsense variant located in exon 25 [c.2836A>T; p.Lys946Ter; chr1:g.196280934T>A; read depth: 42×], predicted to introduce a premature stop codon leading to truncation of the protein. This variant was absent in population databases including gnomAD and 1000 Genomes. In silico prediction tools, including MutationTaster2, suggested a damaging effect, and the affected residue was evolutionarily conserved. The variant was classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria, fulfilling PVS1 (null variant in a gene where loss-of-function is a known disease mechanism) and PM2 (absent in population databases).

Additionally, a heterozygous missense variant in the ARID1A gene (ENST00000324856.13) [c.5570C>T; p.Thr1857Ile] was identified. This variant was absent in major population databases and predicted to be deleterious by multiple in silico tools including SIFT, PolyPhen-2, and LRT. However, due to insufficient clinical and functional evidence, it was classified as a Variant of Uncertain Significance (VUS) based on ACMG criteria (PM2, PP3) [2].

At first follow-up (1-month post-discharge), the child continued to have intermittent breakthrough seizures, though reduced in frequency. Weight gain remained suboptimal, and developmental progress was minimal. At second follow-up (3 months), seizures persisted with clustering episodes, and an additional anti-seizure medication was planned. Brainstem Evoked Response Audiometry (BERA) was planned to assess hearing, and ophthalmological evaluation was advised to rule out visual impairment, given the risk of sensory deficits in epileptic encephalopathies. Orthopedic follow-up was continued for developmental dysplasia of the hip. The child was planned for optimization of anti-seizure therapy, consideration of ketogenic diet, and enrollment in early intervention programs including physiotherapy and developmental therapy. Genetic counseling was provided to the family regarding prognosis, recurrence risk, and the need for parental testing.

Discussion

With the advent of next-generation sequencing, several genetic causes of DEE have been identified, particularly involving ion channel dysfunction, leading to the concept of epileptic channelopathies [3].

Among these, KCNT2 has emerged as a rare but distinct genetic cause of early infantile epileptic encephalopathy [3]. The KCNT2 gene encodes the sodium-activated potassium channel subunit K_Na1.2, which plays an important role in regulating neuronal excitability by contributing to membrane repolarization during periods of increased neuronal firing [4]. Activation of these channels by intracellular sodium provides a negative feedback mechanism to limit excessive neuronal discharge. Pathogenic variants in KCNT2 disrupt this regulatory mechanism, resulting in abnormal neuronal firing patterns and epileptogenesis [5]. Unlike classical potassium channel disorders, KCNT2-related disease demonstrates functional heterogeneity, with both gain-of- function and loss-of-function variants reported in the literature [6]. This variability in channel behavior is thought to contribute to the wide clinical spectrum observed in affected individuals.

Clinically, KCNT2-related encephalopathy is characterized by early-onset seizures, often presenting in the neonatal period or early infancy, and typically evolving into drug-resistant epilepsy [3]. Electroencephalographic findings described in previous reports include multifocal epileptiform discharges and patterns consistent with Epilepsy of Infancy with Migrating Focal Seizures (EIMFS), reflecting a diffuse epileptic network [7]. The evolution of electroencephalographic abnormalities over time, from early background discontinuity to later multifocal and migrating epileptiform activity, suggests a dynamic and progressive disturbance of cortical networks. A major clinical challenge is the early attribution of seizures to metabolic or perinatal causes. Transient metabolic abnormalities, such as hypoglycemia, may coexist and lead to initial diagnostic anchoring. However, persistence of seizures beyond correction and the presence of abnormal background activity should prompt early evaluation for an underlying genetic etiology [8]. This distinction is critical, as delayed diagnosis may impact counseling and long-term management planning.

Comparison with KCNT1-related epilepsies provides further insight into disease mechanisms. Both KCNT1 and KCNT2 encode sodium-activated potassium channels and are associated with similar electroclinical phenotypes, particularly EIMFS. However, KCNT1 mutations are more consistently associated with gain- of-function effects, whereas KCNT2 mutations demonstrate broader functional diversity, suggesting distinct but converging mechanisms of neuronal hyperexcitability [9]. From a therapeutic perspective, seizures associated with KCNT2 mutations are frequently refractory to conventional anti-seizure medications. While quinidine has been explored as a targeted therapy in KCNT1 gain-of-function mutations due to its potassium channel blocking properties, its efficacy in KCNT2-related disorders remains uncertain and likely depends on the specific functional impact of the variant [9]. Extra-neurological features in KCNT2- related disorders have been inconsistently reported, and their significance remains unclear. The presence of dysmorphic features in this case raises the possibility of phenotypic expansion. The identification of an additional variant in ARID1A, a gene associated with Coffin–Siris syndrome, suggests a potential role for genetic modifiers. Although currently classified as a variant of uncertain significance, such co-existing variants may influence phenotypic expression and contribute to blended or overlapping syndromes [10].

The coexistence of a variant in the ARID1A gene introduces the possibility of a blended or modified phenotype. ARID1A encodes a key component of the SWI/SNF chromatin-remodeling complex and is implicated in Coffin–Siris syndrome, characterized by developmental delay, coarse facial features, feeding difficulties, and digital anomalies. The presence of overlapping dysmorphic features in our patient raises the possibility that the ARID1A variant may contribute to phenotypic modulation rather than representing an incidental finding. However, given its current classification as a variant of uncertain significance and the absence of segregation analysis, a definitive causal role cannot be established. Increasing recognition of dual molecular diagnoses in neurodevelopmental disorders suggests that such variants may act additively or modify the primary phenotype, highlighting the importance of comprehensive genomic interpretation [11].

Among reported cases of KCNT2-related encephalopathy (Table 2) [6,10,12-14], the phenotypic spectrum has ranged from Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) and West syndrome to Lennox-Gastaut syndrome, with most patients demonstrating early-onset drug-resistant epilepsy and severe global developmental delay. Both gain-of-function and loss-of-function variants have been implicated, highlighting the functional heterogeneity of KCNT2-related disease. Extra- neurological features such as dysmorphism and hirsutism have been reported in a subset of cases, particularly those with gain-of-function variants at the p.Arg190 residue. However, truncating variants with associated Coffin–Siris–like dysmorphic features, as observed in our patient, have not been previously described, representing a potential expansion of the phenotypic spectrum. Furthermore, the co-occurrence of a second variant in a syndromic gene (ARID1A) has not been reported in prior KCNT2 cases, underscoring the importance of comprehensive genomic interpretation in patients with complex or atypical presentations.

At present, management remains largely supportive, focusing on seizure control, nutritional support, and early developmental interventions. This case contributes to the limited literature on KCNT2-related encephalopathy and highlights several important aspects, including the evolving electroclinical phenotype, the potential for diagnostic delay due to coexisting metabolic factors, and the possibility of genetic interaction influencing phenotypic expression. Further accumulation of cases and functional studies will be essential to refine genotype–phenotype correlations and to explore targeted therapeutic strategies [15]. Compared to previously reported cases (Table 2) [6,10,12-14], our patient uniquely demonstrates a truncating variant with associated dysmorphic features, suggesting a possible expansion of the phenotypic spectrum [16].