A Novel De Novo Gain-of-Function Variant in Neurodevelopmental Disease With Congenital Tremor, Seizures, and Hypotonia.

BACKGROUND AND OBJECTIVES

De novo gain-of-function variants in the gene, encoding the L-type voltage-gated Ca channel Ca1.3, cause a multifaceted syndrome. Patients show variable degrees of autism spectrum disorder, developmental delay, epilepsy, and other neurologic and endocrine abnormalities (primary aldosteronism and/or hyperinsulinemic hypoglycemia). We study here a novel variant [c.3506G>A, NM_000720.4, p.(G1169D)] in 2 children with the same mutation but different disease severity.

METHODS

The clinical data of the study patients were collected. After molecular analysis and cloning by site-directed mutagenesis, patch-clamp recordings of transfected tsA201 cells were conducted in whole-cell configuration. The functional effects of wild-type and mutated channels were analyzed.

RESULTS

One child is a severely affected boy with a novel de novo variant with additional clinical symptoms including prenatal-onset tremor, congenital respiratory insufficiency requiring continuous positive airway pressure ventilation, and sensorineural deafness. Despite episodes of hypoglycemia, insulin levels were normal. Aldosterone:renin ratios as a screening parameter for primary aldosteronism were variable. In the second patient, putative mosaicism of the p.(G1169D) variant was associated with a less severe phenotype. Patch-clamp electrophysiology of the p.(G1169D) variant in a heterologous expression system revealed pronounced activity-enhancing gating changes, including a shift of channel activation and inactivation to more hyperpolarized potentials, as well as impaired channel inactivation and deactivation. Despite retained sensitivity to the Ca channel blocker isradipine in vitro, no beneficial effects of isradipine or nifedipine treatment were observed in the index case.

DISCUSSION

Through this report, we expand the knowledge about the disease presentation in patients with variants and show the novel variant's modulatory effects on Ca1.3 gating.