Spectrum of KV 2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders.

OBJECTIVE: Pathogenic variants in KCNB1, encoding the voltage-gated potassium channel KV 2.1, are associated with developmental and epileptic encephalopathy (DEE). Previous functional studies on a limited number of KCNB1 variants indicated a range of molecular mechanisms by which variants affect channel function, including loss of voltage sensitivity, loss of ion selectivity, and reduced cell-surface expression. METHODS: We evaluated a series of 17 KCNB1 variants associated with DEE or other neurodevelopmental disorders (NDDs) to rapidly ascertain channel dysfunction using high-throughput functional assays. Specifically, we investigated the biophysical properties and cell-surface expression of variant KV 2.1 channels expressed in heterologous cells using high-throughput automated electrophysiology and immunocytochemistry-flow cytometry. RESULTS: Pathogenic variants exhibited diverse functional defects, including altered current density and shifts in the voltage dependence of activation and/or inactivation, as homotetramers or when coexpressed with wild-type KV 2.1. Quantification of protein expression also identified variants with reduced total KV 2.1 expression or deficient cell-surface expression. INTERPRETATION: Our study establishes a platform for rapid screening of KV 2.1 functional defects caused by KCNB1 variants associated with DEE and other NDDs. This will aid in establishing KCNB1 variant pathogenicity and the mechanism of dysfunction, which will enable targeted strategies for therapeutic intervention based on molecular phenotype. ANN NEUROL 2019;86:899-912.

Expanding the phenotype of feingold syndrome-2.

Feingold syndrome-2 has been recently shown to be caused by germline heterozygous deletions of MIR17HG with 10 reported patients to date. Manifestations common to both Feingold syndrome-1 and Feingold syndrome-2 include microcephaly, short stature, and brachymesophalangy; but those with Feingold syndrome-2 lack gastrointestinal atresias. Here we describe a 14-year-old male patient who presented to our Cardiovascular Genetics Clinic with a history of a bicuspid aortic valve with aortic stenosis, short stature, hearing loss, and mild learning disabilities. Upon examination he was noted to have dysmorphic features and brachydactyly of his fingers and toes. His head circumference was 54.5 cm (25th-50th centile) and his height was 161.3 cm (31st centile) after growth hormone therapy. A skeletal survey noted numerous abnormalities prompting suspicion for Feingold syndrome. A comparative genomic hybridization microarray was completed and a ∼3.6 Mb interstitial heterozygous deletion at 13q31.3 including MIR17HG was found consistent with Feingold syndrome-2. Clinically, this patient has the characteristic digital anomalies and short stature often seen in Feingold syndrome-2 with less common features of a congenital heart defect and hearing loss. Although non-skeletal features have been occasionally reported in Feingold syndrome-1, only one other patient with a 13q31 microdeletion including MIR17HG has had non-skeletal manifestations. Additionally, our patient does not have microcephaly and, to our knowledge, is the first reported pediatric patient with Feingold syndrome-2 without this feature. This report illustrates significant phenotypic variability within the clinical presentation of Feingold syndrome-2 and highlights considerable overlap with Feingold syndrome-1.