Table 1 Summary of main genetic and clinical findings of the four patients with de novo missense variants in GABRA4.

From: De novo variants in GABRA4 are associated with a neurological phenotype including developmental delay, behavioral abnormalities and epilepsy

 

Patient 1 [15]

Patient 2 (this study)

Patient 3 (this study)

Patient 4 (this study)

Gender

Female

Female

Male

Male

Current age

8 years

9 years

4 years

10 years

GABRA4 variant (NM_000809.4)

c.899 C > T, p.(Thr300Ile)

c.797 C > T, p.(Pro266Leu)

c.899 C > A, p.(Thr300Asn)

c.634 G > A, p.(Val212Ile)

Confirmed de novo

Yes

Yes

Yes

No

Heterozygous/mosaic

Mosaic

Heterozygous

Mosaic

Heterozygous

In silico predictions

REVEL: pathogenic

AlphaMissense: pathogenic

REVEL: pathogenic

AlphaMissense: pathogenic

REVEL: pathogenic

AlphaMissense: pathogenic

REVEL: uncertain

AlphaMissense: benign

Epileptic seizures

Yes

No

Yes

No

Seizure types

Sleep-related hypermotor seizures, BTCS

N/A

Atonic, myoclonic and focal seizures, BTCS

N/A

EEG

Ictal and interictal epileptiform discharges in right frontal lobe

Sharp waves with right fronto-centro-temporal maximum

Disorganized background, slow spike-and-wave discharges, multifocal spikes

Normal (awake and asleep)

Anti-seizure treatment

LCM, LEV, PB, ZNS, VPA, BRV, LTG

STM, CLB

Multiple ASM, ketogenic diet, epilepsy surgery, callosotomy

N/A

Structural brain abnormalities

Normal MRI

MRI: White matter lesions (parietal, occipital and frontal lobe) indicating delayed myelination

MRI: suspected FCD, delayed myelination; Histology: MOGHE

Normal MRI

Developmental delay

Yes, predominantly speech

Yes, global

Yes, global

Yes, global

Intellectual disability

Borderline

Yes, IQ < 55

Yes, severe (non-verbal)

Borderline

Additional neurological/

behavioral abnormalities

Dyspraxia, deficits affecting attention, executive function, language comprehension, insomnia

ASD with impaired social interaction, aggressive behavior, attention deficits, repetitive behavior/language

Truncal and axial hypotonia, choreiform movements

ADHD and ASD with learning disability, tics, disruptive mood behavior

  1. ADHD attention deficit hyperactivity disorder, ASD autism spectrum disorder, ASM anti-seizure medication, BRV brivaracetam, BTCS bilateral tonic-clonic seizures, CLB clobazam, EEG electroencephalography, FCD focal cortical dysplasia, IQ intelligence quotient, LCM lacosamide, LEV levetiracetam, LTG lamotrigine, MOGHE mild malformation of cortical development with oligodendroglial hyperplasia in frontal lobe epilepsy, MRI magnetic resonance imaging, N/A not applicable, PB phenobarbital, STM sultiame, VPA valproate, ZNS zonisamide.
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