Pathogenic variants in KCNQ2 cause intellectual deficiency without epilepsy: Broadening the phenotypic spectrum of a potassium channelopathy

Abstract

High‐throughput sequencing (HTS) improved the molecular diagnosis in individuals with intellectual deficiency (ID) and helped to broaden the phenotype of previously known disease‐causing genes. We report herein four unrelated patients with isolated ID, carriers of a likely pathogenic variant in KCNQ2, a gene usually implicated in benign familial neonatal seizures (BFNS) or early onset epileptic encephalopathy (EOEE). Patients were diagnosed by targeted HTS or exome sequencing. Pathogenicity of the variants was assessed by multiple in silico tools. Patients' ID ranged from mild to severe with predominance of speech disturbance and autistic features. Three of the four variants disrupted the same amino acid. Compiling all the pathogenic variants previously reported, we observed a strong overlap between variants causing EOEE, isolated ID, and BFNS and an important intra‐familial phenotypic variability, although missense variants in the voltage‐sensing domain and the pore are significantly associated to EOEE (p < 0.01, Fisher test). Thus, pathogenic variants in KCNQ2 can be associated with isolated ID. We did not highlight strong related genotype–phenotype correlations in KCNQ2‐related disorders. A second genetic hit, a burden of rare variants, or other extrinsic factors may explain such a phenotypic variability. However, it is of interest to study encephalopathy genes in non‐epileptic ID patients.

High-throughput evaluation of epilepsy-associated KCNQ2 variants reveals functional and pharmacological heterogeneity

“…Notably, KCNQ2 and certain KCNQ3 variants cause BFNE that is phenotypically indistinguishable. By contrast, other KCNQ2 variants, usually missense, or, more rarely, small inframe deletions arising de novo, were identified in persons with a spectrum of more disabling phenotypes including neonatal onset seizures with subsequent moderate to severe global disability, and later-onset disability with and without seizures (16)(17)(18)(19)(20). Elucidation of genotype-phenotype relationships along the KCNQ2 DEE spectrum has relied on identification and multidisciplinary study of a handful of recurrent KCNQ2 variants.…”

Phenotypic Spectrum in a Family Sharing a Heterozygous KCNQ3 Variant

“…Intrafamilial variability in other monogenic early-onset epileptic encephalopathies has been described in KCNQ2 , SLC2A1 , CLCN4 , and SCN2A. 5,6 The mechanism of the variability is speculated to be attributable to additional germline or somatic variant or environmental factors. Recent studies support the contributions of common variants to the predisposition to generalized epilepsies with different weights from different variants based on the epilepsy subtypes.…”

Behavior of KCNQ Channels in Neural Plasticity and Motor Disorders

“…KCNQ2 is most expressed in the fetal cerebellum, hippocampus, and medulla [ 30 , 31 ]. Genetic mutation in KCNQ2 is often associated with benign familial neonatal seizures and early-onset epileptic encephalopathy [ 9 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. KCNQ3 is also most expressed in the fetal cerebellum, hippocampus, and medulla [ 9 , 30 ].…”

“…KCNQ3 is also most expressed in the fetal cerebellum, hippocampus, and medulla [ 9 , 30 ]. In addition, KCNQ3 mutations are often associated with channelopathies in conjunction with KCNQ2 [ 33 ], but additional literature also supports KCNQ mutations in bipolar disorder [ 36 ] and various thyroid disorders [ 37 ]. Similar to KCNQ1 expression, KCNQ4 is most expressed in the cochlear hair cells but also in trigeminal ganglia [ 14 ].…”