Clinical characteristics.

GNAI1-related neurodevelopmental disorder (GNAI1-NDD) is characterized by mild-to-profound developmental delay and intellectual disability, hypotonia, neurobehavioral and/or psychiatric manifestations, and epilepsy. The neurobehavioral and/or psychiatric manifestations include features of autism spectrum disorder such as stereotypic behaviors (hand flapping, head banging, hand wringing, repetitive noises, teeth grinding, mouthing behaviors), sensory sensitivities, and poor eye contact. Temper tantrums, anxiety, agitation, aggression, and attention-deficit/hyperactivity disorder are also reported. Seizure onset typically occurs within the first six months of life; seizure types include absence, generalized tonic-clonic, and focal-onset impaired awareness. Additional common features include scoliosis, hip dysplasia, feeding difficulties or obesity with insatiable appetite, constipation, and strabismus.

Diagnosis/testing.

The diagnosis of GNAI1-NDD is established in a proband with characteristic clinical features and a heterozygous pathogenic variant in GNAI1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Developmental and educational services; standard epilepsy treatment with anti-seizure medications by an experienced neurologist; physical medicine and rehabilitation, physical therapy, and occupational therapy to include stretching to help avoid contractures and falls; feeding therapy with gastrostomy tube placement as needed; standard treatments for constipation and strabismus; social work support and care coordination as needed.

Surveillance: At each visit, assess developmental progress, educational needs, mobility and self-help skills, growth, nutrition, and family needs, as well as for new seizures or changes in seizures, scoliosis, and constipation; behavioral assessment for autistic features, anxiety, attention-deficit/hyperactivity disorder, and aggressive or self-injurious behaviors as needed.

Genetic counseling.

GNAI1-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. If the GNAI1 pathogenic variant identified in the proband is not identified in either parent, the recurrence risk to sibs is estimated to be 1%-8% because of the possibility of parental germline mosaicism. Once the GNAI1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

GNAI1-related neurodevelopmental disorder (GNAI1-NDD) should be considered in probands with the following clinical and brain MRI findings and family history.

Clinical findings

• Mild-to-profound developmental delay
• Hypotonia
• Mild-to-profound intellectual disability
• Neurobehavioral/psychiatric manifestations (autism spectrum disorder, temper tantrums, anxiety, agitation, aggression, and attention-deficit/hyperactivity disorder)
• Epilepsy (absence, generalized tonic-clonic, focal-onset impaired awareness)

Brain MRI findings

• Atrophy (global)
• Delayed myelination
• Choroid plexus cysts

Family history. Because GNAI1-NDD is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family).

Establishing the Diagnosis

The diagnosis of GNAI1-NDD is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in GNAI1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous GNAI1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with exome sequencing. Other options include use of a multigene panel or genome. Note: Single-gene testing (sequence analysis of GNAI1) is rarely useful and typically NOT recommended. Chromosomal microarray analysis may not be a useful first-line test because, to date, no large pathogenic deletions/duplications have been identified in individuals with GNAI1-NDD.

• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used and yields results similar to an intellectual disability multigene panel with the additional advantage that exome sequencing includes genes recently identified as causing intellectual disability, whereas some multigene panels may not. Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
• An intellectual disability or epilepsy multigene panel that includes GNAI1 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of GNAI1-NDD, some panels for intellectual disability and/or epilepsy may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

GNAI1-related neurodevelopmental disorder (GNAI1-NDD) is characterized by mild-to-profound developmental delay and intellectual disability, hypotonia, neurobehavioral and/or psychiatric manifestations, and epilepsy. To date, at least 26 individuals have been identified with a pathogenic variant in GNAI1 [Deciphering Developmental Disorders Study 2017, Muir et al 2021, Wayhelova et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports. An additional approximately eight individuals with a GNAI1 pathogenic variant have also been reported as part of large cohort studies without phenotypic details [Kosmicki et al 2017, Lim et al 2017, Turner et al 2019, Kaplanis et al 2020, Satterstrom et al 2020, Zhou et al 2022].

Developmental delay has been apparent for all reported individuals with GNAI1-NDD. Developmental delays can range from mild to profound, and the majority of individuals have hypotonia. Sitting and walking milestones are often delayed (20/23 and 21/25, respectively), and some individuals have not or do not achieve sitting or walking (5/23 and 9/25, respectively). Speech can be significantly impaired; many individuals use only a few sounds or words, and ~64% (16/25) of individuals reported remain nonverbal. In general, expressive language skills are more impaired than receptive skills.

Intellectual disability. All individuals with GNAI1-NDD due to a germline variant have intellectual disability ranging from mild to profound (mild/moderate: n=6; severe/profound: n=13). One affected individual who was mosaic for a GNAI1 pathogenic variant did not have intellectual disability [Muir et al 2021].

Autism and other neurobehavioral/psychiatric manifestations. Approximately 80% of reported individuals had one of several neurobehavioral or psychiatric manifestations, including autism spectrum disorder (7/21). Common reported neurobehavioral and psychiatric features include stereotypic behaviors (hand flapping, head banging, hand wringing, repetitive noises, teeth grinding, mouthing behaviors), sensory sensitivities, poor eye contact, temper tantrums, anxiety, agitation, aggression, hyperactivity, and attention-deficit/hyperactivity disorder.

Epilepsy. About 74% of individuals with GNAI1-NDD have had seizures. Age at seizure onset and seizure types are variable. Use of and response to anti-seizure medications (ASMs) is also variable. Some individuals have intractable epilepsy despite multiple ASMs, while others have seizures that resolve [Muir et al 2021].

• Seizure onset typically occurs within the first six months of life (median age of onset is five months), although the earliest seizure onset noted was at 36 hours of life, and the oldest reported onset to date is seven years.
• Seizure types that are most common include absence, generalized tonic-clonic, and focal-onset impaired awareness (~5 individuals each). Some seizures are nocturnal.
• Electroencephalography (EEG) may show slowing, multifocal activity, other epileptic abnormalities, and encephalopathy. There are no specific EEG findings suggestive of GNAI1-related NDD.

Neuroimaging. About half of individuals have abnormal brain MRI imaging. The most common abnormal findings include global atrophy with progressive volume loss, delayed myelination, and choroid plexus cysts.

Musculoskeletal features. Scoliosis has been reported in six individuals. Hip dysplasia was reported in four individuals, with at least two requiring osteotomy.

Feeding. Feeding difficulties can be present, requiring modified diets (e.g., liquid diet) and/or gastrostomy tube feedings. Obesity and insatiable appetite have also been observed (n=7).

Gastrointestinal issues. Some individuals have constipation.

Ophthalmologic involvement. Strabismus has occurred in a few individuals but does not appear to be common.

Facial features. If present, dysmorphic features are nonspecific in individuals with GNAI1-NDD.

Prognosis. Information about progression and/or regression of neurologic findings is not known. It is also unknown whether life span in individuals with GNAI1-NDD is abnormal; all individuals reported thus far have been children and adolescents. One reported individual is alive at age 18 years [Muir et al 2021], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Prevalence

Fewer than 30 individuals have been reported to have GNAI1-NDD. Two large studies provide estimates of the prevalence (0.6 in 100,000) [Gillentine et al 2022] and incidence (1.3 in 100,000) [López-Rivera et al 2020].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GNAI1-NDD, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

GNAI1-related neurodevelopmental disorder (GNAI1-NDD) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Most probands reported to date with GNAI1-NDD whose parents have undergone molecular genetic testing have the disorder as a result of a de novo heterozygous or mosaic GNAI1 pathogenic variant [Muir et al 2021].
• A proband with GNAI1-NDD may have the disorder as the result of a pathogenic variant inherited from a parent with germline or somatic and germline mosaicism. In one family reported to date, the proband inherited a GNAI1 pathogenic variant from a parent who was determined to be mosaic (6% minor allele fraction in DNA extracted from leukocytes) [Muir et al 2021].
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and to inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    * A parent with somatic and germline mosaicism for a GNAI1 pathogenic variant may theoretically be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the GNAI1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
• If the GNAI1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1%-8% because of the possibility of parental germline mosaicism [Myers et al 2018, Muir et al 2021].

Offspring of a proband. Each child of an individual with GNAI1-NDD has a 50% chance of inheriting the GNAI1 pathogenic variant. (There are no reports of individuals with GNAI1-NDD who have reproduced; however, many are not yet of reproductive age.)

Other family members. Given that all probands with GNAI1-NDD reported to date have the disorder as the result of a GNAI1 pathogenic variant that occurred de novo in the proband or in a mosaic parent, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the GNAI1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing is possible. Risk to future pregnancies is presumed to be low as the proband most likely has a de novo GNAI1 pathogenic variant. There is, however, a recurrence risk (~1%-8%) to sibs based on the possibility of parental germline mosaicism [Myers et al 2018, Muir et al 2021]. Given this risk, prenatal and preimplantation genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

GNAI1 encodes guanine nucleotide-binding protein G(i) subunit alpha-1 (Gαi1), which is an inhibitory subunit of G protein complex that can bind GDP and GTP [Neves et al 2002]. When bound to GDP, it forms an inactive heterotrimer with beta (β) and gamma (γ) G protein subunits. Once a G protein-coupled receptor (GPCR) is activated, GDP is exchanged for GTP, causing the α subunit to dissociate from the βγ complex, so that each subunit (α and βγ) is active and can act on downstream signaling pathways [Oldham & Hamm 2008]. Several genes encoding G protein subunits have been implicated in neurodevelopmental disorders and epilepsy [Petrovski et al 2016, Feng et al 2017, Nakamura et al 2013] (see also GNB1 Encephalopathy).

Gαi1 couples negatively to adenylyl cyclase (AC) to inhibit the production of cyclic adenosine monophosphate (cAMP) with downstream impact on the MAPK/ERK pathway, while their G protein βγ partners mediate the Akt-mTOR and other pathways, which are important in regulation of cell proliferation and growth [Cao et al 2009, Marshall et al 2018].

To date, at least 17 pathogenic variants in GNAI1 have been identified, including 13 missense variants, three small in-frame deletions of one to four amino acids, and one variant predicted to cause a frameshift that would not be expected to undergo nonsense-mediated decay based on its location. Six missense variants and one coding deletion are recurrent in more than one unrelated individual, and most missense and in-frame deletion variants (10/16) impact residues in the GDP/GTP binding pocket.

Mechanism of disease causation. To date, the impact of reported pathogenic variants on protein function (gain vs loss of function) is not known. Although GNAI1 is predicted to be intolerant to loss-of-function variants [Muir et al 2021], de novo disease-causing truncating variants in GNAI1 have not yet been identified.

Author Notes

Mefford Laboratory
St Jude Children's Research Hospital
Center for Pediatric Neurological Disease Research
Department of Cell & Molecular Biology
262 Danny Thomas Place, Mail Stop 340
Memphis, TN 38105-3678
www.stjude.org/research/labs/mefford-lab

Dr Mefford ([email protected]) and her team are actively involved in clinical and translational research regarding GNAI1-related neurodevelopmental disorder (GNAI1-NDD). They would be happy to communicate with persons who have any questions regarding diagnosis of GNAI1-NDD or other considerations, such as GNAI1 variants of uncertain significance.

Revision History

• 1 August 2024 (sw) Review posted live
• 8 September 2023 (hm) Original submission

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