Phenotypic characterization of KCTD3‐related developmental epileptic encephalopathy

Abstract

The association between KCTD3 gene and neurogenetic disorders has only been published recently. In this report, we describe the clinical phenotype associated with 2 pathogenic variants in KCTD3 gene. Seven individuals (including one set of monozygotic twin) from 4 consanguineous families presented with developmental epileptic encephalopathy, global developmental delay, central hypotonia, progressive peripheral hypertonia, and variable dysmorphic facial features. Posterior fossa abnormalities (ranging from Dandy-Walker malformation to isolated hypoplasia of the cerebellar vermis) were consistently observed in addition to other variable neuroradiological abnormalities such as hydrocephalus and abnormal brain myelination. One patient also had a multicystic kidney. Whole exome sequencing revealed 2 probably pathogenic homozygous variants in KCTD3 gene that fully segregated with the disease. KCTD3 gene belongs to a family of accessory subunits that regulate the biophysical properties of ion channels, and is highly expressed in the kidney and brain. In this largest series to date on KCTD3-mutated patients, we show that biallelic loss of function mutations in KCTD3 lead to a consistent phenotype of developmental epileptic encephalopathy and abnormal cerebellum on brain imaging.

The emerging role of the KCTD proteins in cancer

“…While KCTD3 has been associated with neurogenetic and neurodevelopmental disorders [ 1 , 91 ], no correlation with cancer has been reported so far.…”

KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

“…Homozygous KCTD3 mutations were identified in three additional families, one harboring the same frameshift mutation (c.1036_1073del, p.P346Tfs*4), and the other two harboring a missense mutation (c.166C > T, p.Arg56*) . KCTD3 patients exhibit global developmental delay, seizures, and cerebellar hypoplasia …”

“…90 KCTD3 patients exhibit global developmental delay, seizures, and cerebellar hypoplasia. 88,90 The biological function of KCTD3 protein has not been investigated in-depth, but one study provides some evidence that links KCTD3 with the nervous system. Mouse Kctd3 was identified as a binding partner of Hcn3 (hyperpolarization-activated cyclic nucleotide-gated channel) in a yeast two-hybrid screen.…”

Intellectual Disability and Potassium Channelopathies: A Systematic Review

“…Kctd3 and Hcn3 co-localize in the cerebellum, hypothalamus, and midbrain and Kctd3 upregulates the expression of Hcn3 (Cao-Ehlker et al, 2013). HCN3 modulates synaptic strength and cellular excitability (Biel et al, 2009;Huang et al, 2011). Faqeih et al (2018 reported seven cases with severe GDD, epilepsy, and cerebellar hypoplasia, of which five were carrying P346Tfs * 4 and the other two were carrying R56 * mutations.…”