Clinical characteristics.

GNB1 encephalopathy (GNB1-E) is characterized by moderate-to-severe developmental delay / intellectual disability, structural brain abnormalities, and often infantile hypotonia and seizures. Other less common findings include dystonia, reduced vision, behavior issues, growth delay, gastrointestinal (GI) problems, genitourinary (GU) abnormalities in males, and cutaneous mastocytosis.

Diagnosis/testing.

The diagnosis of GNB1 encephalopathy (GNB1-E) is established in a proband by identification of a heterozygous GNB1 pathogenic variant by molecular genetic testing.

Management.

Treatment of manifestations: Developmental delay / intellectual disability, hypotonia, seizures, poor vision, behavior issues, growth delay, GI problems, GU abnormalities in males, and cutaneous mastocytosis are managed as per standard care.

Surveillance: Follow up of the common manifestations at each clinic visit.

Genetic counseling.

GNB1-E is inherited in an autosomal dominant manner and is typically caused by a de novo pathogenic variant. If the GNB1 pathogenic variant identified in the proband is not identified in one of the parents, the risk to sibs is low but greater than that of the general population because of the possibility of parental germline mosaicism. Once the GNB1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

GNB1 encephalopathy (GNB1-E) should be considered in individuals with the following clinical findings.

Clinical findings

• Moderate to profound developmental delay (DD) or intellectual disability (ID); AND
• One or more of the following features presenting in infancy or childhood:
  • Generalized hypotonia of infancy that can evolve to hypertonia and spasticity
  • Feeding disorder and difficulties with weight gain in infancy
  • Movement disorder (dystonia, tics, ataxia, and chorea)
  • Epilepsy (including generalized, focal, and mixed epilepsy and infantile spasms)
  • Behavior problems (repetitive and stereotypic behaviors, attention-deficit/hyperactivity disorder [ADHD], and/or autism spectrum disorder [ASD])
  • Macrocephaly
  • Slow growth
  • Vision impairment (optic atrophy and cortical visual impairment) and/or abnormal eye movements (strabismus, nystagmus)
  • Gastrointestinal issues (chronic constipation, cyclic vomiting, gastroesophageal reflux disease [GERD], and/or abdominal distention with cramps)
  • Craniofacial anomalies (cleft palate, craniosynostosis)
  Note: When present, dysmorphic features are nonspecific.

Establishing the Diagnosis

The diagnosis of GNB1 encephalopathy (GNB1-E) is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in GNB1 on molecular genetic testing (see Table 1). Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Clinical Description

GNB1 encephalopathy (GNB1-E) is characterized by developmental delay / intellectual disability, structural brain abnormalities, and often infantile hypotonia and seizures. Other less common findings include dystonia, reduced vision, behavior issues, growth delay, gastrointestinal problems, genitourinary abnormalities in males, and cutaneous mastocytosis.

To date, 58 individuals have been identified with GNB1-E caused by a heterozygous GNB1 pathogenic variant [Firth et al 2009, Petrovski et al 2016, Steinrücke et al 2016, Brett et al 2017, Lohmann et al 2017, Hemati et al 2018, Peng et al 2018, Szczałuba et al 2018, Jones et al 2019, Endo et al 2020]. Of note, one individual with a milder phenotype was mosaic for a GNB1 pathogenic variant [Hemati et al 2018]. The following description of the phenotypic features associated with GNB1-E is based on these reports.

Developmental delay (DD) and intellectual disability (ID). Moderate-to-severe DD has been reported in almost all individuals with GNB1 variants. Severe neurodevelopmental deficit, marked by an inability to walk independently, has been reported in about 50% of individuals. Of note, one individual started walking independently at age nine years following intensive physical therapy. Hemiplegia, severe dyskinetic quadriplegia, and spastic diplegia have each been reported in one individual [Petrovski et al 2016, Endo et al 2020].

Speech delay is common; about 40% of individuals are nonverbal. Of note, in two individuals with normal hearing, alternative means of communication (such as sign language) improved communication.

Developmental regression was documented in three individuals. One became visually inattentive, hypotonic, and lethargic at age eight weeks, and had further developmental regression with the onset of infantile spasms at age seven months. Two others had regression of verbal skills by age three years [Petrovski et al 2016].

ID, ranging from mild to severe, has been reported in about 74% of individuals. ID was not reported in two individuals older than age six years [Lohmann et al 2017]. Of note, several individuals with GNB1 variants were too young at the time of publication to have an informative assessment of cognitive function, and cognitive abilities were not consistently documented in older individuals.

The presence or absence of DD and ID was not documented in one individual in the DECIPHER database [Firth et al 2009] or in the four reported parents with GNB1 variants [Firth et al 2009, Lohmann et al 2017].

Abnormal brain MRI findings include abnormal or delayed myelination, abnormal corpus callosum, cerebral volume loss, ventriculomegaly, and bilateral polymicrogyria.

Abnormal muscle tone. Generalized hypotonia of infancy can evolve into hypertonia and spasticity over time.

Epilepsy. Seizure types can include tonic, absence, myoclonic, generalized tonic-clonic, and focal seizures, as well as epileptic spasms. Importantly, GNB1 has been identified as a candidate gene for West syndrome [Peng et al 2018], and several individuals with GNB1-E have had West syndrome or infantile spasms [Hemati et al 2018, Endo et al 2020].

EEG may be normal in the first years of life. Hypsarrhythmia, generalized epileptiform discharges or multifocal epileptiform discharges (especially from the temporal regions) may develop and become abundant in sleep.

Movement disorders. Dystonia, the most common movement disorder reported, ranges in severity from mild dystonic positioning of the fingers to generalized dystonia. Myoclonus-dystonia and occasional status dystonicus with dystonic hypertonia have each been reported in one individual [Jones et al 2019, Endo et al 2020]. Tics, ataxia, and chorea have also been seen.

Sensory impairment

• Vision. Nystagmus is the most common ophthalmologic finding, reported in 36% of individuals. Nystagmus can be horizontal and vertical, rotatory, and multivectorial; it has been reported to improve with age in two individuals [Hemati et al 2018]. Other eye movement abnormalities include strabismus, upward gaze palsy, gaze deviation, slow ocular pursuit response, continuous reverse ocular dipping, and ophthalmoplegia.
  Abnormal vision due to cortical visual impairment or optic atrophy has been reported in 11% of individuals, including one individual considered to be legally blind. Ocular albinism and possible rod-cone dystrophy were each observed once [Hemati et al 2018]; neither individual was reported to have other genetic variants that could explain these findings.
• Hearing. Severe sensorineural hearing loss, both unilateral and bilateral, has been reported. One individual had hypoplasia of the right cochlear nerve in addition to profound sensorineural hearing loss of the right ear; another had both conductive and severe sensorineural hearing loss [Hemati et al 2018].

Behavior issues include repetitive and stereotypic behaviors, attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD).

Growth. Poor feeding and poor weight gain in the neonatal period have been reported in about 50% of individuals with GNB1-E with a documented neonatal history. Of these, most (8/11) outgrew their feeding difficulties and poor weight gain. Overall, persistent growth delay was reported in 20% of individuals.

Other associated features (inconsistently documented in publications):

• Gastrointestinal problems. Recurrent constipation, cyclic vomiting, gastroesophageal reflux disease, hepatic vein anomaly, and distended abdomen with cramps
• Genitourinary abnormalities in males. Undescended testes, bifid scrotum, duplicated renal collecting system, and hydronephrosis, each observed in fewer than three individuals.
• Cardiovascular abnormalities. Ventricular septal defect, duplicated superior vena cava
• Craniofacial anomalies. Cleft palate has been reported in five individuals [Petrovski et al 2016, Brett et al 2017, Hemati et al 2018]. Craniosynostosis was reported in three individuals [Lohmann et al 2017]. Both macrocephaly and microcephaly have been reported. When present, other dysmorphic features are nonspecific.
• Cutaneous mastocytosis, a condition in which apparently normal mast cells accumulate in the skin, was reported in four infants, including monozygotic twins [Hemati et al 2018, Szczałuba et al 2018]. Urticaria pigmentosa is the most common presentation of mastocytosis. Cutaneous mastocytosis in children younger than age five years is generally benign, requires no treatment, and can disappear by puberty; however, in rare instances it can progress to systemic mastocytosis which can affect almost all organs [Theoharides et al 2015]. Note: While gain-of-function variants in c-KIT have been observed in cutaneous mastocytosis, exome sequencing on fibroblasts from the monozygotic twins with GNB1-E with mastocytosis did not identify any additional potentially causative variants or regions of loss of heterozygosity. No somatic variants in KIT or JAK2 were detected [Hemati et al 2018].
• Hypothyroidism. Congenital peripheral hypothyroidism and subclinical hypothyroidism have each been reported once [Petrovski et al 2016, Szczałuba et al 2018]. The true incidence of hypothyroidism is not known.
• Malignancy. Acute lymphoblastic leukemia has been reported in one individual with a de novo germline GNB1 pathogenic variant [Brett et al 2017]. Because somatic GNB1 pathogenic variants affecting the same residues have been detected in individuals with hematologic malignancies [Yoda et al 2015], the possible association of germline GNB1 pathogenic variants and an increased risk for malignancies has been raised [Petrovski et al 2016].

Prognosis. Regression of skills has been documented in only a few individuals with GNB1-E. Life expectancy and common causes of death are not known, as most individuals reported are children or young adults. Of note, the cause of death in a child who died at age four years was unknown [Hemati et al 2018].

Although an increased risk for malignancies has been suggested [Petrovski et al 2016], acute lymphoblastic leukemia has been reported in only one individual with a germline GNB1 variant [Brett et al 2017].

The absence of congenital anomalies associated with high morbidity and mortality suggests a favorable long-term prognosis with appropriate support and management. The authors are aware of three individuals with GNB1-E older than age 18 years reported in the medical literature [Firth et al 2009, Petrovski et al 2016], as well as a 38 year old [unpublished]. In addition, four parents with a GNB1 variant have been reported [Firth et al 2009, Lohmann et al 2017], 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 under-recognized and under-reported.

Genotype-Phenotype Correlations

Many recurrent GNB1 variants have been associated with phenotypic variability among individuals with the same variant. Although not conclusive, the following genotype-phenotype correlations have been proposed:

• Fifty-five percent of individuals with dystonia had a p.Ile80 substitution (p.Ile80Thr or p.Ile80Asn). This possible genotype-phenotype correlation was initially suggested by Petrovski et al [2016].
• Three of the four individuals with cutaneous mastocytosis had the p.Ile80Thr variant [Hemati et al 2018].
• A genotype-phenotype correlation between the p.Ile80Thr variant and severe axial hypotonia or hypotonic quadriplegia has been suggested [Endo et al 2020].

Penetrance

Most probands reported to date with GNB1-E whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GNB1 pathogenic variant. Penetrance is expected to be 100%.

Prevalence

Fifty-eight individuals with GNB1-E caused by a heterozygous pathogenic GNB1 variant have been reported to date.

No increased prevalence of GNB1 encephalopathy has been reported in any specific population or ethnic group. No founder variants are known.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GNB1 encephalopathy, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Surveillance

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

GNB1 encephalopathy (GNB1-E) is inherited in an autosomal dominant manner and is typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Most probands reported to date with GNB1-E whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GNB1 pathogenic variant.
• Rarely, individuals diagnosed with GNB1-E have inherited a GNB1 pathogenic variant from a parent. Three unrelated ethnically diverse individuals were reported to have inherited the p.Arg96Leu variant from a parent [Lohmann et al 2017] and one individual inherited the p.Thr243Ala variant from her mother [Firth et al 2009]. Clinical information on parents was not available.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the GNB1 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is that the proband inherited a pathogenic variant from a parent with germline mosaicism. Although theoretically possible, no instances of parental germline mosaicism have been reported to date.
• Note: A parent with somatic and germline mosaicism for a GNB1 pathogenic variant may 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 has the GNB1 pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• If the proband represents a simplex case (i.e., the only affected family member) and the GNB1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is presumed to be greater than that of the general population because of the theoretic possibility of parental mosaicism. In a study assessing mosaicism in the apparently asymptomatic parents of children with developmental and epileptic encephalopathy, the frequency of parental somatic and (inferred) germline mosaicism was found to be 10% [Myers et al 2018].

Offspring of a proband. Each child of an individual with GNB1-E has a 50% chance of inheriting the GNB1 pathogenic variant.

Other family members. Given that most probands with GNB1-E reported to date have the disorder as a result of a de novo GNB1 pathogenic variant, 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

If neither parent has a GNB1 pathogenic variant, the risk to future pregnancies is presumed to be low as the proband most likely has a de novo GNB1 pathogenic variant. There is, however, a recurrence risk to sibs based on the theoretic possibility of parental germline mosaicism [Myers et al 2018]. Given this risk, prenatal testing and preimplantation genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Heterotrimeric G protein complexes function as cellular signal transducers for G protein-coupled receptors (GPCRs). They are composed of an alpha (Gα), a beta (Gβ), and a gamma subunit (Gγ). GPCR activation catalyzes a GDP-to-GTP exchange on the Gα subunit, leading to the dissociation of Gα from the obligate dimer Gβγ. Both Gα and Gβγ then bind and regulate a wide variety of downstream effectors.

GNB1 encodes the guanine nucleotide-binding protein subunit beta-1(Gβ1). Effectors of Gβγ include ion channels, phospholipases, adenylyl cyclases, and PI3K and MAPK signaling pathways [Smrcka 2008, Khan et al 2013, Khan et al 2016]. A bioluminescence resonance energy transfer (BRET) assay has been used to test the functional consequence of disease-associated GNB1 missense variants [Lohmann et al 2017].

Mechanism of disease causation. The mechanism of disease in GNB1-E is not fully understood. Most reported variants are missense variants [Firth et al 2009, Petrovski et al 2016, Steinrücke et al 2016, Brett et al 2017, Lohmann et al 2017, Hemati et al 2018, Szczałuba et al 2018, Jones et al 2019, Endo et al 2020] with specific properties:

• Recurrent missense changes
• The vast majority of those tested occurred de novo.
• Thirty different missense variants have been reported so far, with 73% of these occurring in exons 6 and 7 (NM_002074.4). The most common variant reported to date is Ile80Thr in exon 6 (seen in 20% of affected individuals).
• Many reported germline missense variants occurred at the same codons and/or were identical to somatic missense variants identified in tumor samples [Yoda et al 2015] (see Cancer and Benign Tumors).
• In functional studies, the abnormal Gβ1 protein impaired function of the G protein heterotrimer [Lohmann et al 2017].

Because most pathogenic variants appear to occur at the surface of interaction between the Gβ1 and Gα subunits or downstream effectors, it is believed that perturbation of this interaction will affect the regulation of the downstream signaling pathways. This may have gain-of-function, dominant-negative, or loss-of-function consequences on the regulation of these pathways.

Research on GNB1 haploinsufficiency is inconclusive. Although several loss-of-function variants have been associated with disease [Lohmann et al 2017, Endo et al 2020, Schultz-Rogers et al 2020], the pathogenicity of these variants remains unclear. A functional study of a splice-site variant and a frameshift variant showed reduction/absence of protein expression and, thus, loss of protein function in a BRET assay [Schultz-Rogers et al 2020], suggesting haploinsufficiency as the disease mechanism. In contrast, in one study the phenotype of a heterozygous knockout mouse did not differ from that of the wild type [Okae & Iwakura 2010], whereas the phenotype of a mouse heterozygous for a human pathogenic missense variant was similar to that of human GNB1-E [Colombo, personal observation], which is inconsistent with haploinsufficiency. Thus, the pathogenicity of loss-of-function variants remains to be clarified.

Cancer and Benign Tumors

Acute lymphoblastic leukemia has been reported in one individual with a de novo germline GNB1 pathogenic variant [Brett et al 2017].

Recurrent somatic GNB1 variants have been reported in various cancer types. Because many of the tumor-derived missense variants occurred at the same codons (e.g., p.Lys78Gln, p.Lys78Glu, and p.Arg96His [Yoda et al 2015]) and/or were identical to the missense variants associated with GNB1-E (e.g., p.Ile80Thr, p.Ile80Asn, and p.Asp118Tyr [Yoda et al 2015]; Table 6), the possible association of germline GNB1 pathogenic variants and an increased risk for malignancies has been raised [Petrovski et al 2016].

Author Notes

Anya Revah-Politi is a certified genetic counselor at the Institute for Genomic Medicine and at the Precision Genomics Laboratory at Columbia University Irving Medical Center. She holds a faculty appointment as Assistant Professor of Genetic Counseling in Pathology and Cell Biology and in the Institute for Genomic Medicine at Columbia University Irving Medical Center.

Tristan T Sands is an Assistant Professor of Neurology in the Division of Child Neurology and at the Institute for Genomic Medicine at Columbia University Irving Medical Center.

Sophie Colombo is an Associate Research Scientist in the Goldstein Laboratory at the Institute for Genomic Medicine at Columbia University Irving Medical Center.

David B Goldstein is the John E Borne Professor of Medical and Surgical Research (in Genetics and Development, in the Institute for Genomic Medicine, and in Neurology), Professor of Medical Sciences (in Medicine), and Director of Institute for Genomic Medicine, at Columbia University Irving Medical Center.

Kwame Anyane-Yeboa is a Professor of Pediatrics and serves as Chief at the Division of Clinical Genetics at Columbia University Irving Medical Center. He is a frequent collaborator in the Institute for Genomic Medicine.

Columbia University Institute for Genomic Medicine website: www.igm.columbia.edu

Acknowledgments

We acknowledge the contribution of the DECIPHER Consortium. The DECIPHER study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk. Funding for the project was provided by the Wellcome Trust.

Revision History

• 15 April 2021 (aa) Revision: incorporated data from Myers et al [2018], Schultz-Rogers et al [2020]
• 5 March 2020 (bp) Review posted live
• 28 June 2019 (kay) Original submission

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