Expansion of the Mutation and Phenotype Spectrum of the GABRA2-related developmental and epileptic encephalopathy78

doi:10.21203/rs.3.rs-4773390/v1

Background

Developmental and epileptic encephalopathy 78 is a severe neurological disease characterized by intractable seizures and severe intellectual disability (ID). It was discovered in 2019 as a autosomal dominant genetic disease caused by heterozygous mutation in the GABRA2 gene(* 137140) which located on chromosome 4p12. So far,only 8 patients with 7 deleterious missense variants in the GABRA2 gene have been reported.

Materials and methods

In this study, Using Trio-Whole Exome Sequence, we discovered five novel GABRA2 variants in five unrelated patients belong to five different families. Furthermore, we systematically described all 13 patients’ clinical features and molecular genetics.

Result

Identified five novel deleterious variants in GABRA2 gene within five patients,one frameshift variant(c.988_c.989insTTATG, p.Glu330Valfs*22), four missense variants(c.644T > C, p.Leu215Ser; c.862A > G, p.Thr288Ala; c.166C > T, p.Arg56Trp; c.460C > G, p.Leu154Val). These patient cohort presents a complex array of neurological and developmental challenges, with a spectrum ranging from severe motor and cognitive impairment to varying degrees of seizure frequency and type, as well as resistance to pharmacological treatments. The variability in clinical presentation highlights the need for individualized approaches to treatment and care

Conclusion

In summary, Seizures were a phenotype observed in all patients, while there were other additional variable phenotypes. We identified five novel variants of the GABRA2 gene using Trio-whole exome sequence for the fist time in China, This study broadened the genetic and phenotypic spectrum of the GABRA2 gene

Biological sciences/Genetics/Clinical genetics

Biological sciences/Genetics/Medical genetics

GABRA2 gene

Developmental and epileptic encephalopathy 78

neurological disease

whole exome sequencing

genetic and phenotypic spectrum

Developmental and epileptic encephalopathy 78 (DEE78, OMIM: 618557) is a severe neurological condition characterized by the emergence of intractable seizures within the initial days or months of an individual's life, subsequently leading to severe intellectual disability (ID). Additional variable manifestations encompass microcephaly, cortical visual impairment, hypotonia, and aberrant movements such as spasms, resulting in an inability to ambulate^[1].DEE78 was discovered in 2019 as a autosomal dominant disorder caused by heterozygous mutation in the GABRA2 gene.

GABA, also known as gamma-aminobutyric acid, serves as the major inhibitory neurotransmitter in the brain, playing a critical role in the regulation of neuronal excitability and the maintenance of a balance between excitation and inhibition in the central nervous system. It achieves this by binding to GABA receptors, which are a group of proteins involved in GABAergic neurotransmission in the mammalian central nervous system. This group includes three subtypes: GABA-A, GABA-B, and GABA-C receptors. Among these, GABA-A receptors, which are heteropentameric and ligand-gated anion channels, serve as the specific site for GABA's action^[1,2].

The GABRA2 gene is located on chromosome 4p12,and consists of nine exons, encoding GABA α2 subunits that encompass 451 amino acids.To date, a total of seven missense variations in the GABRA2 gene have been documented in eight patients from seven families with DEE78. Among these variations, six are de novo, while one variation is present in two siblings from the same family, inherited from their father, who carries a mosaic variant^[1,3-5].

Trio-WES(Trio-whole exome sequencing) has been widely utilized in the diagnostic process of neurological disorders, demonstrating significant cost-effectiveness. In this study, we employed Trio-WES (trio whole-exome sequencing) to identify five previously unreported de novo variations (c.644T>C, p.Leu215Ser; c.988_c.989insTTATG, p.Glu330Valfs*22; c.862A>G, p.Thr288Ala; c.166C>T, p.Arg56Trp; c.460C>G, p.Leu154Val) in the GABRA2 gene among five unrelated Chinese patients, comprising two females and three males. Furthermore, this study represents the first documentation of GABRA2 gene variations in the Chinese population. We systematically collected and reviewed clinical data and imaging investigations for all 13 affected individuals, thereby expanding the phenotype and mutation spectrum of DEE78. Additionally, our findings establish a robust molecular genetic basis for future researchers to further investigate the underlying mechanisms of the disease and explore novel therapeutic approaches.

Whole-exome capture and sequencing

Written informed consent have been accepted from their parents before using their clinical information and undergoing genetic analysis in this study. And this study was approved by the Ethics Committee of Shengjing Hospital Affiliated to China Medical University.

DNA was submitted for trio whole-exome sequencing (trioWES) to Chigene (Beijing) Translational Medical Research Center Co. Ltd. (Beijing Quanpu Medical Laboratory Co., Ltd.). The DNA samples were fragmented (main peak 430bp, range from 300bp to 600bp) by ultrasonic waves and tested by Agilent 2100 (Agilent Technologies Co., Ltd.). Fragmented DNA was hybridized with IDT xGen® Exome Research Panel v2.0 (IDT, IA, USA;https://www.idtdna.com/) to capture the exome. The xGen® Exome Research Panel v2.0 covers the coding and splicing regions (~42.5Mb) for 19,396 genes in human genome. The effective molecular concentration (25ul, >10nM) was evaluated using q-PCR for all three exome capture libraries. Whole-exome sequencing was performed using DNBSEQ-T7 (Mgi Tech Co., Ltd, Shenzhen, China) for pair-end sequence at a read-length of 150bp to coverage >99%, depth from 100× to 170× of the targeted regions, and depth from 192× to 413× of the GABRA2 gene.

Data analysis and variant discovery

Sequencing reads were processed and fastq files were generated according to manufacturer’s instructions. Sequences were mapped to GRCh37/hg19 using BWA; SNVs and Indels were called by GATK software. Variants were filtered based on read depths (DP < 4), allele frequency (AF > 0.2), genotype quality (GQ > 35); inheritance status was assessed by family genotypes. Candidate variants were annotated for functional effect predtiction using several tools, including Provean, SIFT, Polyphen2_HDIV, Polyphen2_HVAR (http://www.bork.embl-heidelberg.de/PolyPhen/),mutationtaster(http://www.mutationtaster.org),M-CAP,REVEL(https://sites.google.com/site/revelgenomics/),CADD((http://cadd.gs.washington.edu/), and the databases for MAFs annotation include dbSNP,1000 Genome Project,ExAC,ESP,gnomAD,and an inhouse database from Chigene Co., Ltd(contains WES/WGS data from 20,0000 individuals). SpliceAI, MaxEntScan,GTAG,dbscSNV were used for predicting variants that potentially affect splicing. GERP,phastCons,phyloP were used for predicting the conservation of the variants. Finally, the variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines.

In silico analysis

Amino acid conservation analysis were performed using Ugene.Gene structure and domain model diagrams were created using IBS 2.0: Illustrator for Biological Sequences(https://ibs.renlab.org/#/server)^[6]. Protein sequence characteristics(for example: transmembrane regions, signal peptide sequences, and variations) were drawed using Protter, an online software tool for protein visualization

(https://wlab.ethz.ch/protter/start/).The protein 3D images were generated using PyMOL(PyMol Molecular Graphics System, Schrödinger, LLC).

Clinical features

Patient 1, a male child, was born with a birth weight of 4100g and is the first child (G1P1) of healthy parents. The mother was 28 years old and the father was 29 years old at the time of his birth. No abnormalities were observed during the neonatal period. However, at the age of 1 year, the patient was diagnosed with a right-sided testicular hydrocele. At 2 years and 1 month, he experienced febrile convulsions, which recurred six times over the next two years. At the age of four, the patient experienced an unprovoked fall accompanied by minimal clonus in both upper limbs, which resolved within a few seconds without any noticeable impairment of consciousness. Subsequently, ten months later, the patient experienced another fall while walking. Brain magnetic resonance imaging (MRI) and ambulatory electroencephalography (AEEG) conducted during interictal periods yielded normal results.().

Patient 2, a 10-year-old female, was delivered via cesarean section and had a birth weight of 3850g. Her mother was 20 years old and her father was 19 years old at the time of delivery. She is the first child (G1P1) of her parents. During a subsequent follow-up, she demonstrated deficiencies in object tracking and sound tracking abilities. Additionally, she had not yet achieved any developmental milestones and experienced her initial visible generalized tonic-clonic seizure at the age of 4 months. An electroencephalogram revealed the presence of spinous slow waves in the right anterior and middle temporal regions (Fig.1).Subsequently, she was prescribed oral solutions of sodium valproate and levetiracetam, as well as topiramate capsule, 4 months later, the seizure was achieved. At the age of 2 years, she showed obvious lack of language, rigid behavior, lack of interest and reaction to human voices, she also began to walk unsteadily and independently. After the age of 3 years, her parents described that she can speak only several single words, noticeable attention deficit, and an increase in activity and impulsivity. Brain MRI showed normal findings at the age of 4 months,19 months, and 3 years.

Patient 3, a 10-year-old male, was born to a mother with a history of two instances of embryonic development cessation. Despite being born in good health, he exhibited delayed developmental milestones, such as walking at the age of 2, and experienced his first febrile convulsion at the age of 5. Subsequently, he suffered from falls and generalized tonic-clonic seizures, which were successfully managed with the administration of Valproate.

Patient 4, a 6-year and 10-month-old female, had an unremarkable birth and developmental history. However, starting at 14 months of age, she experienced five episodes of febrile seizures.

Patient 5 was a 1-year,10-month-old boy. He has a severe global developmental delay, characterized by a lack of eye contact even with close individuals and unable to walk or speak. He started experiencing partial seizures at the age of 3 months and they remain very frequent despite taking VPA,TPM,VPA orally.

Figure 1 shows the electroencephalogram of patient2 and patient3;

Table 1 shows the clinical features and variants of all our patients and Literature patients reported before.

Table1：The clinical features and variants of all patients

f

Patient1

This study

Patient2

This study

Patient3

This study

Patient4

This study

Patient5

This study

Patient6^[3]

Patient7^[3]

Patient8^[3]

Patient9^[3]

Patient10^[3]

9’s sister

Patient11^[4]

Patient12^[1]

Patient13^[5]

Age/sex

7y5m/M

10y/F

10y/M

6y10m/F

1y10m/M

5.5m/F

32m/F

5 y/F

17y/M

13y/F

10m/M

11y/F

10y/F

variant

c.166C>T

p.Arg56Trp

c.862A>G

p.Thr288Ala

c.644T>C

p.Leu215Ser

c.988_989insTTATG

p.Glu330Valfs*22)

c.460C>G

p.Leu154Val

c.851T>C p.Val284Ala

c.871C>G p.Leu291Val

c.788T>C p.Met263Thr

c.975C>A p.Phe325Leu

c.1003A>C p.Asn335His

c.875C>A p.Thr292Lys

c.839C>T

p.Pro280Leu

Inheritance

De novo

Father (mosaic)

De novo

Pregnancy/ neonatal mensurations

N / N

Two embryos stop developing with unknown causes before the patient were borned（G1,G2)/ N

N / N

Excess fetal hiccuping / N

N / N

NA

N / N

Neonatal findings

N

Hypotonia, failure to thrive, respiratory distress

Severe hypotonia

Hypotonia, respiratory distress

Jaundice

NA

Severe hypotonia, neonatal hypothermia

NA

N

Age of walking

N

Around 36m

24m

N

Can't walk independently

Too young

Not able

14m

Around 12 m

Too young

Not able

NA

Current language ability

N

Very poor，several single words

N

Severe

Too young

Not able

Very low

Decreased ability

Slightly decreased

Too young

Not able

Decreased Comprehension,expression

Cognitive development

N

Severe

N

Severe

Profound

Severe

Moderate

Mild/moderate

Severe

Profound

Sever

ASD

No

Yes

NO

No

Yes

Too young

NA

Yes

No

Too young

NA

Yes

Age at seizure onset

2y1m

4m

5y

1y2m

3m

1m

1d

2d

17y

2y

10w

6w

15m

Seizure type at onset

Fever seizure,Generalized tonic-clonic

Generalized tonic-clonic

Fever seizure,drop seizure, and generalized tonic-clonic

Fever seizure

Focal seizure

Ocular revulsion

Ocular version,Focal clonic

Generalized tonic-clonic

Complex partial

Mastication and blinking

Clustered focal seizures, spasms

EIEE

Seizure types during disease course

Fever seizure,and drop seizure

Generalized tonic-clonic

Fever seizure,drop seizure, and generalized seizure

Fever seizure

Focal seizure

Absences, clonic

Behavioral arrests, clonic, tonic

Spasm, clonic

Generalized tonic-clonic

Complex partial

Hypertonus, grimacing and facial flushing, partial tonic with clonic eyelid movements

Tonic, tonic-clonic and myoclonic

Tonic with upward eye deviation, or eye and head deviation to either side

Status epilepticus

No

Yes

No

Yes

NA

N

No

Frequency of seizures，max

2/w

10/d

4/w

Only had 5

6/d

20/d

15/d

10/d

Only had 3

NA

At least once daily

N

Current AETs

No

LEV

VPA

No

OXC,TPM,VPA

VPA, PHT

PB, CLB, CLN, VPA, TPM

Sabril, hydrocortisone

LTG

OXC

TPM, GVG

VPA, PB, CLB

VPA, CLB

Pharmacoresistance

No

Yes

No with treatment

Partial response

Yes

N

Head circumference, SD

0

-1

-2

-3.75

0

Neurological examination

N

Hypotonia, ADHD

N

Global developmental delay

Hypotonia, pyramidal syndrome

Severe hypotonia, reduced reflexes, cortical visual impairment

Hypotonia

Features of autism

N

Severe hypotonia, choreiform movements

Severe hypotonia, spasticity, cortical visual impairment

Hypotonia, ADHD, developmental delay

MRI: age / main abnormalities

2y1m/N

4m, 19m, 3y/N

5y/N

1y/N

3m/N

23m/generalized brain atrophy, abnormal myelination; CC thin and short

2y/N

17y/N

13y/N

10w/N

9y/

hypomyelination

Normal,19 m

EEG: age / main abnormalities

2y1m, 2y10m, 4y1m, 4y11m/N

4m/spinous slow waves in the anterior and middle temporal regions

5y, widespread spinous slow waves discharging during sleep

1y/N

3m/A large number of multifocal spikes, sharp waves, sharp slow waves, and fast waves rhythms were observed during sleep

2m/isolated spike,rapid rythm

28 m / multifocal spikes right and left hemisphere; generalized spikes and polyspikes

8d/discontinous, diffuse spike

17y/normal, bilateral frontal/ fronto-central sharp activity, but not truly epileptiform

NA

Fast background activity and left centro-parietal spikes

2y/slow and disorganized back ground with multifocal epileptic form discharges

Onset of epilepsy was normal,but later investigations showed slow and irregular background activity, without paroxysmal activity

N: normal

NA：can’t obtain the information because of Lost access or other reasons

Molecular Findings

In the study, we identified five variants in GABRA2 among the five unrelated families. These variants included four missense variants (c.166C>T, p.Arg56Trp; c.862A>G, p.Thr288Ala; c.644T>C, p.Leu215Ser; c.460C>G, p.Leu154Val) and one frameshift variant (c.988_c.989insTTATG, p.Glu330Valfs*22). None of these variants were previously reported and they were not found in various databases such as dbSNP, 1000 Genome Project, ExAC, ESP, gnomAD, and our inhouse database. To validate their authenticity, Sanger sequencing was performed (Figure 2). According to ACMG standards and guidelines, these variants were rated as Uncertain significance,Pathogenic or likely Pathogenic(PS2_Moderate+PM2_Supporting+PP2+PP3=VUS; PS2_Moderate +PM1+PM2_Supporting+PP2 +PP3=LP; PS2_Moderate +PM1+PM2_Supporting +PP2+PP3=LP; PVS1+ PS2_Moderate +PM2_Supporting=P; PS2_Moderate+PM1+PM2_Supporting+PP2+PP3=LP; respectively).

In silico Analysis result

GABRA2 is a transmembrane protein with three main domains: Signal peptide (pink), Neu_chan_lig-bd(green), and Neu_chan_memb(purple); M1,M2,M3,M4 are the four transmembrane areas. (Figure 3A,3B). So far, all 7 reported variants are located in the Neu_chan_memb domain, two of the five variants identified in this study are also located in this domain, the second/third transmembrane areas(M2/M3) to be more exactly, the other three located in Neu_chan_lig-bd domain(Figure 3B). Protein conservation analysis in 15 species revealed all of these five variants were located in highly conserved regions.(Figure 3C).

The 3D structure of wild type and mut. type GABRA2: Arg56(wild) vs Trp56(mut.), Thr288(wild) vs Ala288(mut.), Leu215(wild) vs Ser215(mut.), Leu154(wild) vs Val154(mut.) see Figures 4A-4F, show hydrogen bond and protein sequence changes.

.Our study presents an additional five cases, marking the 9th-13th instances of DEE78 and the first reported cases in China.

The cohort comprises five pediatric patients, ranging in age from one year and ten months to ten years old, consisting of three boys and two girls. These genetic alterations encompass both missense mutations (patients 1, 2, 3, 5) and a frameshift mutation.

Epileptic seizures are a common thread uniting all patients, yet they exhibit considerable variability in presentation and frequency. Febrile seizures were observed in patients 1, 3, and 4, while they were absent in patients 2 and 5. Instead, these two patients experienced more frequent episodes, with patient 2 enduring seizures up to 10 times daily, and patient 5, six times daily. Notably, patient 5 has shown resistance to medication, necessitating a regimen of multiple antiepileptic drugs, including oxcarbazepine (OXC), topiramate (TPM), and valproic acid (VPA).Profound cognitive impairments are evident in patients 2 and 5, both of whom have been diagnosed with Autism Spectrum Disorder (ASD). Motor development is similarly affected, as illustrated by patient 5's need for assistance to walk and patient 2's delayed milestone of independent walking, achieved at approximately 36 months. Patient 2 also presents with hypotonia and Attention Deficit Hyperactivity Disorder (ADHD), while patient 5 is affected by Global Developmental Delay.Neurological evaluations for patients, with the exception of patients 2 and 5, have yielded normal findings. Electroencephalography (EEG) has uncovered notable abnormalities in brain wave patterns during sleep for patients 2, 3, and 5. In contrast, patients 1 and 4 exhibit fewer EEG irregularities. At the core, the five cases share de novo mutations in the GABRA gene, alongside a range of epileptic symptoms. However, there are pronounced differences in seizure type, frequency, cognitive and motor development, and demonstrated EEG and neurological anomalies. The conditions of patients 2 and 5 are particularly severe, with marked cognitive deficits, developmental delays, and in the case of patient 5, significant drug resistance.Our cohort exhibits characteristics consistent with previously reported instances, such as the presence of de novo mutations in the GABRA gene and the occurrence of epileptic seizures. With the exception of case 4, all involve missense mutations, and interestingly, the frameshift mutation does not align with a more severe clinical presentation. Our patients did not present with similar drug resistance or severe clinical manifestations, such as respiratory difficulty and pronounced hypotonia in the neonatal period, as noted in prior reports. Cases 9 and 10 deserve special attention, as the mutations are paternally derived (mosaic) and are associated with relatively less severe cognitive impairment and more manageable epilepsy.

GABRA2, encodes GABA α2 subunits. GABA is an inhibitory neurotransmitter in the brain, and abnormalities in it’s synthesis, transport, decreased or loss activity, as well as mutations in the genes encoding it, can be potential affect neuronal activity then lead to various neurological disorders and symptoms. Some studies have found a correlation between GABRA2 polymorphisms and psychiatric or behavioural disorders such as alcohol addiction and polydrug abuse ^[7-10], anxiety and depression^[11-12], aggressive behaviour^[13]. In recent years, GABRA2 has been reported to cause Developmental and epileptic encephalopathy 78 and seven variations have been reported^[1,3-5].We further detect five novel variations in five unrelated families in this study,one frameshift variant,four missense variants:c.166C>T,p.Arg56Trp;c.862A>G,p.Thr288Ala;c.644T>C,p.Leu215Ser;c.988_c.989insTTATG,p.Glu330Valfs*22);c.460C>G,p.Leu154Val. Thus, there are twelve variations over the world now.

The in silico analysis conducted in this study reveals that GABRA2 is a transmembrane protein consisting of three primary domains and four transmembrane regions. Among the twelve identified variants of the GABRA2 gene, they were found to be localized within two domains, namely Neu_chan_lig-bd and Neu_chan_memb. These variants potentially impact the binding of the GABRA2 protein with its ligand and the transportation of GABA. Notably, all five variants identified in this study are situated within the highly conserved regions. Specifically, the variants p.Arg56Trp and p.thr288Ala result in alterations to hydrogen bonding, while the variant c.988_c.989insTTATG leads to partial errors in the translation of the amino acid sequence and truncation of the protein sequence.

In conclusion, our research has broadened the genetic and phenotypic spectrum of the GABRA2 gene, and contributed to the ongoing investigation of the relationship between these genetic variations and the resulting disease phenotype. Moreover, this study holds promise in enhancing our comprehension of GABRA2-related disorders, as well as improving the diagnosis, treatment, and prognosis for affected patients. These insights may also offer potential targets for therapeutic interventions in these relevant diseases.

Data availability statement:

The datasets generated and/or analyzed during the current study are available in the ClinVar repository. Accession numbers are Submission ID: SUB14676795, SUB14674668, SUB14676879(in processing), SUB14676841(in processing), and SUB14677004(in processing).

Ethics statement：

The studies involving human participants were reviewed and approved by the Ethics Committee of Shengjing Hospital Affiliated to China Medical University (code: 2023PS987K). The research was performed in accordance with the Declaration of Helsinki. Written informed consent to participate in this study was provided by the participants' legal guardian. Written informed consent was also obtained from the minors' legal guardian for the publication of any potentially identifiable images or data included in this article. All methods were performed in accordance with the relevant guidelines and regulations.

Author contributions：

TY.G and PC.W wrote the manuscript. WH, ZHM, ZZL and ZJM provided clinical information. All authors read and approved the ﬁnal manuscript.

Funding：

No funding.

Acknowledgments

We would like to thank the family of the reported cases for their participation in this study.

Conﬂict of interest

Authors Pengchao Wang,Weiyue Gu were employed by Chigene (Beijing) Translational Medical Research Center Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or ﬁnancial relationships that could be construed as a potential conﬂict of interest.

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No competing interests reported.

Expansion of the Mutation and Phenotype Spectrum of the GABRA2-related developmental and epileptic encephalopathy78

Status:

Version 1

Abstract

Background

Materials and methods

Result

Conclusion

Figures

Introduction

Materials and methods

Results

Discussion

Declarations

References

Additional Declarations

Status:

Version 1