Phenotypic Diversity in GNAO1 Patients: A Comprehensive Overview of Variants and Phenotypes

Abstract

GNAO1 disorder is a rare autosomal dominant neurodevelopmental syndrome that is clinically manifested by developmental delay, (early onset) epilepsy, and movement disorders. Clinical symptoms appear very heterogeneous in nature and severity, as well as the response of GNAO1 patients to available medication varies. Pathogenic GNAO1 variants have been found mainly scattered throughout the gene although certain mutation hotspots affecting the function of the encoded Gαo proteins exist. GNAO1 variants only partially explain the diverse phenotypic spectrum observed but full stratification has been hampered by the limited number of patients. The aim of this review was to generate a comprehensive overview of the germline variants in GNAO1 and provide insight into the phenotypic diversity of the GNAO1 disorder. We compiled a list of 398 GNAO1 germline variants. In addition, we provide the GNAO1 variants and associated phenotypes of 282 GNAO1 patients reported in case reports, whole genome sequencing studies, genetic variant databases, and 8 novel GNAO1 patients that were not described before. This has resulted in a list of 107 (likely) pathogenic GNAO1 variants. Available phenotypic data was utilized to quantitatively assess the genetic and phenotypic diversity of the GNAO1 disorder and discuss the outcomes. This inventory forms the basis for a GNAO1 variant database that will be updated continuously. Moreover, it will aid genetic diagnostics, medical decision-making, prognostication, and research on the mechanisms underlying the GNAO1 disorder.

Figure 1

Structure of GNAO1 and the encoded proteins. (a) Overview of the GNAO1 locus (chr16: 56,190,000-56,360,000 hg38) containing GNAO1A and GNAO1B. (b) Alignment of the GNAO1 encoded human Gαo1 and Gαo2 protein sequences. The protein sequence before the start of the alignment (AA242) is shared by Gαo1 and Gαo2. AAs in the helical domain are shown in black, the linker region in red, and the GTPase region in blue. Indicated are the alpha helices and beta strands that were determined on the basis of the AlphaFold structure (A0A3Q1MSI3) and other important regions, whose positions were derived from Johnston et al. [8]. (c) Predicted structure of bovine Gαo1 by AlphaFold (A0A3Q1MSI3). The helical domain is dark gray, and the GTPase part is depicted in the colours for the per-residue confidence score (pLDDT) given by Alphafold. Blue (very high: pLDDT > 90), cyan (high: 90 > pLDDT > 70) and yellow (low: 70 > pLDDT > 50).

Figure 2

Classical view of Gαo signaling. Overview of the different stages of the Gαo activation cycle and the canonical signaling of GPCRs through Gαo. Of note and not depicted: Gαo likely performs also GPCR-independent functions like KEDLR-mediated activation of RAB4 that is independent of Gβγ [57].

Figure 3

Enumeration of pathogenic and likely pathogenic GNAO1A germline variants. (a) Distribution of (likely) pathogenic GNAO1 variants across Gαo1 that have been found in 282 GNAO1 patients. Variants are either (likely) pathogenic variants or variants provoking a typical GNAO1 phenotype. If additional, indisputably unique, patients (submissions) were found in ClinVar these were included as well. Indicated functional Gαo domains were derived from [8]. Mutation hotspots are indicated by dotted lines. (b) Number and frequency of GNAO1A variants in mutation hotspots that are caused by either CpG deamination (red bar) or other mutation routes (gray bar).

Figure 4

Enumeration of epilepsy in GNAO1 patients. Frequency at which an epileptic phenotype is observed in GNAO1 patients (n = 232) and distribution of the type of DEE. The type of DEE was deduced from the available EEG description and age of onset. Unfortunately, a detailed description of DEE subtypes and EEG recordings was not always available. Furthermore, overlapping symptoms between subtypes make it more difficult to correctly group DEE subtypes. (b) Number of patients with DEE (n = 50) caused by missense mutations or indels. Percentages of GNAO1 patients with DEE are indicated for AA variants that have been found in >5 DEE patients. Location of the P-loop and switch I, II, and III regions is indicated. Infantile epileptic spasms syndrome (IESS), early infantile DEE (EIDEE), epilepsy of infancy with migrating focal seizures (EIMFS).

Figure 5

Evaluation of MD in GNAO1 patients. (a) Frequency at which an MD phenotype is observed in GNAO1 patients (n = 223) and distribution of the type of MD symptoms (n = 157 MD patients). A single patient may exhibit multiple MD symptoms. Frequencies of MD subtypes are calculated from 157 GNAO1 MD patients, for which a more detailed description was available. (b) Number of patients with MD caused by missense mutations or variants affecting splicing which result in AA insertions or truncated out-of-frame products. Percentages of GNAO1 patients with MD are indicated for AA variants that have been found in >4 MD patients. Location of the P-loop and switch I, II, and III regions is indicated. Mutation hotspots are depicted as red circles. Of note, depicted percentages and absolute numbers are only an indication as movement symptoms may change over time or may arise only later in childhood after the publication of the initial case report.

Figure 6

Evaluation of phenotypes in patients with a mutation hotspot variant. Absolute number of patients with a certain phenotype. Epilepsy = gray bar; MD = dark blue bar and mix of epilepsy; and MD = light blue bar.

Figure 7

Prevalence and heterogeneity of other clinical manifestations in GNAO1 patients. (a) Frequency of developmental delay in GNAO1 patients (n = 204) (left), with the distribution of mild, moderate, and severe gradations (right) (n = 84 patients). (b) Frequency of speech problems in GNAO1 patients (n = 111). c) Structural changes in the brains of GNAO1 patients (n = 145). This number is likely an underrepresentation as MRI data from investigations at a later age are often not publicly available.

Figure 8

Heterogeneous responses to available medication in GNAO1 patients. (a) Heterogeneity in response to antiepileptic drug (AED) in GNAO1-DEE patients (n = 53). (b) Heterogeneous response to medication in GNAO1-MD patients (n = 70). Of note, MD is often progressive in GNAO1 patients, and a full response does not necessarily mean a lifelong symptom-free status.