The constitutional gain-of-function variant p.Glu1099Lys in NSD2 is associated with a novel syndrome.

NSD2 dimethylates histone H3 at lysine 36 (H3K36me2) and is located in the Wolf-Hirschhorn syndrome (WHS) critical region. Recent descriptions have delineated loss-of-function (LoF) variants in NSD2 with a distinct disorder. The oncogenic missense variant p.Glu1099Lys occurs somatically in leukemia and has a gain-of-function (GoF) effect. We describe two individuals carrying p.Glu1099Lys as heterozygous de novo germline variant identified by exome sequencing (ES) of blood DNA and subsequently confirmed in two ectodermal tissues. Clinically, these individuals are characterized by intellectual disability, coarse/ square facial gestalt, abnormalities of the hands, and organomegaly. Public cell lines with NSD2 GoF variants had increased K36me2, DNA promoter methylation, and dysregulated RNA expression. NSD2 GoF caused by p.Glu1099Lys is associated with a novel phenotype different from WHS and Rauch-Steindl syndrome (RAUST).

De novo BK channel variant causes epilepsy by affecting voltage gating but not Ca2+ sensitivity.

Epilepsy is one of the most common neurological diseases and it causes profound morbidity and mortality. We identified the first de novo variant in KCNMA1 (c.2984 A > G (p.(N995S)))-encoding the BK channel-that causes epilepsy, but not paroxysmal dyskinesia, in two independent families. The c.2984 A > G (p.(N995S)) variant markedly increased the macroscopic potassium current by increasing both the channel open probability and channel open dwell time. The c.2984 A > G (p.(N995S)) variant did not affect the calcium sensitivity of the channel. We also identified three other variants of unknown significance (c.1554 G > T (p.(K518N)), c.1967A > C (p.(E656A)), and c.3476 A > G (p.(N1159S))) in three separate patients with divergent epileptic phenotypes. However, these variants did not affect the BK potassium current, and are therefore unlikely to be disease-causing. These results demonstrate that BK channel variants can cause epilepsy without paroxysmal dyskinesia. The underlying molecular mechanism can be increased activation of the BK channel by increased sensitivity to the voltage-dependent activation without affecting the sensitivity to the calcium-dependent activation. Our data suggest that the BK channel may represent a drug target for the treatment of epilepsy. Our data highlight the importance of functional electrophysiological studies of BK channel variants in distinguishing whether a genomic variant of unknown significance is a disease-causing variant or a benign variant.