A NGS-Targeted Autism/ID Panel Reveals Compound Heterozygous GNB5 Variants in a Novel Patient

Abstract

Homozygous and compound heterozygous pathogenic variants in GNB5 have been recently associated with a spectrum of clinical presentations varying from a severe multisystem form of the disorder including intellectual disability, early infantile developmental and epileptic encephalopathy, retinal abnormalities and cardiac arrhythmias (IDDCA) to a milder form with language delay, attention-deficit/hyperactivity disorder, cognitive impairment, with or without cardiac arrhythmia (LADCI). Approximately twenty patients have been described so far; here we report a novel case of a 2.5-year-old female who is a compound heterozygote for a frameshift and a missense variant in the GNB5 gene. Her clinical presentation is consistent with a moderate phenotype, corroborating the direct correlation between the type and pathogenic mechanism of the GNB5 genetic variant and the severity of related phenotype.

Keywords: GNB5; IDDCA; LADCI; cardiac arrhythmia; cognitive impairment.

FIGURE 1

(A) Family pedigree investigated in this study. Filled symbols represent: hypotonia (bottom left quarter), severe sick sinus syndrome (SSS; top left quarter), seizure (bottom right quarter), and intellectual disability (ID; top right quarter). (B) Distribution of the GNB5 variants (NM_006578) across the gene with exons indicated by gray boxes. The frameshift variants are designated in bold, missense variants are in gray, and nonsense variants are in black. The number of patients with each variant is indicated in parentheses. (C) Schematic representation of the GNB5 protein with Coiled coil and WD-40 repeats domains.