Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures

Abstract

Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein subunit beta-1, Gβ. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p = 7.1 × 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gβ binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gβγ interaction (resulting in a constitutively active Gβγ) or through the disruption of residues relevant for interaction between Gβγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

“…Two subjects had BCAs likely associated with genomic disorders: one involved a 2p21-p13.3 duplication encompassing NRXN1, and the other disrupted the imprinted 11p15 region associated with Silver-Russel syndrome (MIM#180860). In the remaining four subjects with Likely Pathogenic BCAs, the rearrangement truncated genes that were associated with developmental disorders, yet only activating or missense mutations had been previously reported ( e.g., CACNA1C and GNB1) 52,53 , proposing a dosage sensitive model for these loci. Based on these results, we interpreted that 12.5% (31/248) of subjects harbored a BCA that likely contributed to the developmental phenotype by disrupting potentially novel candidate genes or disease mechanisms.…”

The expanding spectrum of movement disorders in genetic epilepsies

“…112 Defects in autophagy, another innate cellular system of cargo disposal and recycling, also lead to mixed epilepsy/ movement disorder phenotypes. [121][122][123] Gb1 is the bsubunit of a guanine nucleotide-binding protein that forms heterotrimeric complexes with G protein subunits a and c. Gb1 is involved in the same cellular pathway as GNAO1 and interacts with GNAL (encoded by the gene mutated in DYT25 dystonia), 122 which might provide a causative link to the combined epilepsy and movement disorder phenotype seen in these patients. Beta-propeller protein-associated neurodegeneration manifests with epilepsy of multiple seizure types (febrile, focal with impaired awareness, absences, atonic, tonic, epileptic spasms, GTCS, and myoclonic, or even DEE or West syndrome), 114 MECP2-like hand wringing stereotypies, and, later in the disease course, neurological regression, dystonia, and prominent parkinsonian features.…”

Myoclonus‐dystonia caused by GNB1 mutation responsive to deep brain stimulation

“…Since the initial description, 46 cases of GNB1 have been published, and movement disorders have been documented in 18 cases . Dystonia is most common and has been associated with missense mutations causing p.Ile80 substitution, but myoclonus, chorea, athetosis, and/or tics are also noted . Only Steinrucke and colleagues have detailed the phenomenology of the movement disorder in a report of a 15‐year‐old girl with generalized dystonia and myoclonus and a missense mutation adjacent to our patient's, c.353A>G, p.(Asp118Gly).…”

“…GNB1 is a recently described neurodevelopmental disorder with hypotonia and seizures being the most consistent features . Since the initial description, 46 cases of GNB1 have been published, and movement disorders have been documented in 18 cases .…”