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

Natascia Malerba,Giuseppe Merla,Katherine Keating,Shelley Towner,William Wilson,Gabriella Maria Squeo

doi:10.3389/fgene.2018.00626

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.

Highlights

G protein coupled receptors (GPCR), by activating heterotrimeric guanine nucleotide-binding proteins (G-proteins), control an array of cellular functions (Smrcka, 2008)
Others and we identified homozygous or compound heterozygous variants in the GNB5 gene that are associated with either IDDCA (MIM#617173) or LADCI (MIM#617182), in which the severity of the phenotype correlates with the type of the genetic variant (Lodder et al, 2016; Shamseldin et al, 2016)
Sequence and copy number alterations were reported according to the Human Genome Variation Society (HGVS) and International System for Human Cytogenetic Nomenclature (ISCN) guidelines, respectively

Summary

Introduction

G protein coupled receptors (GPCR), by activating heterotrimeric guanine nucleotide-binding proteins (G-proteins), control an array of cellular functions (Smrcka, 2008). Ligand binding of a GPCR acts as guanine-nucleotide exchange factors (GEFs) that activate trimeric G-proteins, leading the exchange of GDP in GTP on the Gα subunit, its dissociation from Gβγ dimer, and thereby enabling both Gα and Gβγ subunits to modulate a wide range of downstream signaling (Gilman, 1987). GPCR cascade is ended by the regulator of G-protein signaling (RGS) proteins, which accelerate the GTP hydrolysis on the Gα subunits, thereby promoting their inactivation. A hallmark of R7-RGS protein organization is their association with Gβ5, encoded by GNB5, a divergent member of the beta subunits of heterotrimeric G proteins (Cabrera et al, 1998; Makino et al, 1999)

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