Abstract
Heterozygous pathogenic variants in GATAD2B gene have been related to the GATAD2B‐associated neurodevelopmental disorders (GAND) characterized by neurodevelopmental delay with predominant language impairment, infantile hypotonia, macrocephaly, ophthalmological abnormalities, and dysmorphic facial features with nonspecific findings on brain magnetic resonance imaging (MRI). Occasionally, affected individuals exhibit drug responsive epilepsy, psychiatric disorders, and other extra‐neurological comorbidities. We report a patient carrying a de novo heterozygous missense variant in GATAD2B gene. She presents a developmental and epileptic encephalopathy (DEE) with drug‐resistant atypical absences. An extensive review of the literature did not show any similar phenotype. Our report broadens the electroclinical spectrum related to GATAD2B pathogenic variants and supports the inclusion of this monogenic etiology among the genetic causes of epilepsy with drug‐resistant atypical absences, a group with few known genetic etiologies.
Plain Language Summary
We describe a patient with drug‐resistant atypical absences caused by a pathogenic variant in the GATAD2B gene. Mutations in the GATAD2B gene should be considered among the rare monogenic causes of atypical absences.
Keywords: epilepsy, GATAD2B, heterozygous variants, neurodevelopmental delay
Key points.
Pathogenic variants in the GATAD2B gene are linked to neurodevelopmental disorders. Drug‐responsive epilepsy is occasionally reported.
We describe a patient with a missense GATAD2B variant presenting with developmental and epileptic encephalopathy, featuring drug‐resistant atypical absences.
This report supports including GATAD2B variants among the genetic causes of epilepsy with drug‐resistant atypical absences.
1. INTRODUCTION
The GATA zinc finger domain containing 2B gene (GATAD2B; MIM 614998; 1q21.3) encodes a transcriptional protein repressor called GATAD2B or p66‐beta. This protein acts as a component of the Nucleosome Remodeling and Deacetylase (NuRD) Complex, involved in genomic integrity, stem cell differentiation, DNA repair, and neurodevelopment. 1 , 2 This complex manages transcription through two distinct enzyme activities: histone deacetylase and ATP‐dependent nucleosome remodeling. 3
Loss‐of‐function heterozygous pathogenic variants in GATAD2B including deletions, nonsense, truncating frameshift, and splice‐site mutations were related to the GATAD2B‐associated neurodevelopmental disorder (GAND; MIM 615074). A few pathogenic missense variants affecting the GATAD2B highly conserved domains CR1 or CR2 have been detected in individuals with GAND and predicted to impair protein functions. 1
Individuals with GAND present distinct phenotypic features including intellectual disability (ID), language disorders, ophthalmological abnormalities, macrocephaly, infantile hypotonia, dysmorphic face features, and nonspecific findings on brain magnetic resonance imaging (MRI). Polyhydramnios, neonatal feeding difficulties, cardiac abnormalities, seizures, and psychiatric disorders are reported less frequently. 1 , 4
We identified a de novo heterozygous missense variant affecting the highly conserved CR1 domain of GATAD2B protein, in a patient who presents drug‐resistant atypical absence seizures, and intellectual disability (ID) with a predominant language impairment. We validated this phenotype as expanding the spectrum of GATAD2B after an extensive literature review.
2. METHODS
We performed a whole genome sequencing in the proband and her unaffected parents (trio analysis). We describe the GATAD2B variant according to HGVS variant nomenclature guidelines (http://varnomen.hgvs.org/), using the reference sequence RefSeq NM_020699.4.
We performed an extensive literature review using the following search terms through PubMed: (“GATAD2B phenotypes” OR “GATAD2B gene”). We selected all studies published in English including case reports manuscripts that reported patients carrying confirmed GATAD2B pathogenic or likely pathogenic variants. The collected data encompassed demographic information, patients' phenotypes, diagnostic testing performed including the description of detected variant and the treatment administered (Tables 1 and S1).
TABLE 1.
Clinical, neuroimaging, and molecular findings in patients carrying pathogenic GATAD2B variants including literature review and our case.
| Literature review N = 94 | The present patient | |
|---|---|---|
| Sex |
Female 24/94 (26%) Male 20/94 (21%) NA 50/94 (53%) |
Female |
| Age at last examination, y | Range 0.7–35 (Mean age: 7) | 15.3 |
| Inheritance |
De novo 88/94 (94%) Inherited via somatic mosaicism from one healthy parent who presented the variant in ≤15% of the whole blood cells DNA 6/94 (6%) |
De novo |
| Variant type |
Truncating frameshift 43/94 (45%) Nonsense 18/94 (19%) Deletions 17/94 (18%) Splice‐site 8/94 (9%) Missense 8/94 (9%) |
Missense |
| Neurodevelopmental disorders |
Moderate to severe intellectual disability or developmental delay 92/94 (98%) Predominant language impairment 85/85 (100%) Can pronounce single words 64/85 (75%) Non‐verbal 16/85 (19%) Can use short sentences 5/85 (6%) ASD 9/94 (9%) ADHD 4/94 (4%) |
Moderate intellectual disability Can use short sentences |
| Neurological examination |
Childhood hypotonia 69/94 (73%) Macrocephaly at last examination 60/94 (64%) Wide based/unstable gait 42/85 (49%) Fine motor and coordination difficulties 7/85 (8%) Non ambulatory 5/85 (6%) Spasticity 2/94 (2%) |
Fine motor and coordination difficulties Unstable based gait |
| Psychiatric disorders |
Sleep disorder 9/94 (9%) Anxiety disorder 6/94 (6%) Irritability and aggressiveness 5/94 (5%) Inappropriate laughter 4/94 (4%) OCD 2/94 (2%) |
Stereotypies and hyperkinetic movements |
|
Epilepsy Age at seizure onset Seizure type |
16/94 (17%) Range (1 month–5 years) Mean age 15 months Focal seizures 2/16 (12%) Primary generalized tonic–clonic seizure 3/16 (19%) NA 11/16 (69%) |
yes 3 m Atypical absence seizures |
| Response to ASMs |
Drug resistance 4/16 (25%) Control with ASMs 12/16 (75%) |
Drug resistance |
| EEG abnormalities |
2/16 (12%) |
Yes Bi‐frontal epileptic discharges |
| Dysmorphisms |
77/94 (82%) Prominent forehead 62/77 (80%) Hypertelorism 49/77 (67%) Pointed chin 48/77 (62%) Prominent/bulbous nasal tip 48/77 (62%) Blonde hair 23/77 (30%) Narrow palpebral fissures 17/77 (22%) Broad mouth 14/77 (18%) Ear anomalies 14/77 (18%) Thin upper lip 12/77 (15%) Short Philtrum 10/77 (13%) Downturned mouth 10/77 (13%) Clinodactyly 4/77 (5%) Syndactyly 1/77 (1%) |
Prominent forehead, pointed chin, bulbous nasal tip and bilateral syndactyly of the second and third toes |
| Ophthalmologic features |
Strabismus 63/94 (67%) Astigmatism 23/94 (24%) Hypermetropia 17/94 (18%) Myopia 10/94 (10%) Anisocoria 7/94 (7%) Optic nerve hypoplasia 6/94 (6%) |
/ |
| Other comorbidities |
Polyhydramnios 22/94 (23%) Feeding difficulties 12/94 (13%) Cardiac abnormalities 7/94 (7%) Constipation 6/94 (6%) Scoliosis 2/94 (2%) Deafness 2/94 (2%) |
Polyhydramnios, feeding difficulties |
| RMI abnormalities |
43/94 (46%) White matter signal abnormalities 19/43 (44%) Enlarged extra‐axial spaces/ ventriculomegaly 15/43 (35%) Delayed myelination 7/43 (16%) Thin corpus callosum 3/43 (7%) Pontocerebellar hypoplasia 1/43 (2%) |
White matter signal abnormalities |
Abbreviations: ADHD, attention‐deficit hyperactivity disorder; ASD, autism spectrum disorder; ASM, antiseizure medication; EEG, electroencephalogram; m, month; NA, not available; OCD, obsessive‐compulsive disorder; RMI, resonance magnetic imaging; y, year.
3. RESULTS
3.1. Case report
The patient is a 15‐year and 3‐month‐old girl born at 38 + 4 weeks of gestation, from healthy French non‐consanguineous parents. During the sixth month of gestation, ultrasound examination revealed a polyhydramnios, and the patient underwent an amniotic reduction of 1.5 liters of excess fluid. Karyotype performed on amniotic fluid was normal. Birthweight was 3080 g (25th Percentile), length 48.5 cm (25th‐50th Percentile), and head circumference 35 cm (75th Percentile). She showed early neonatal feeding difficulties and a transient respiratory distress necessitating oxygen therapy for 12 h without assisted ventilation.
She presented dysmorphic facial features encompassing prominent forehead, pointed chin, bulbous nasal tip, and bilateral syndactyly of the second and third toes. She presented a global neurodevelopment delay since the first months. She achieved head control at 11 months of age and independent walking at 2 years of age.
At the age of 3 years, she started to experience 10–30 seizures per day characterized by behavioral arrest and upward deviation of the eyeballs sometimes associated with a sudden atonic fall. Seizures lasted around 10 s, occurred mainly at awakening and were exacerbated by tiredness. Lamotrigine (LTG) and then valproate (VPA) were administered without any efficacy on seizure frequency. At the age of 4 years, she presented severe intellectual delay, hyperkinetic movements, and stereotypies including hand‐mouthing and lip‐biting.
At the age of 5 years, she showed an unstable gait, fine motor skills delay and started to pronounce her first words. At this stage, her cranial circumference was 51 cm (85th percentile). Seizures were always daily and characterized by behavioral arrest, up gaze, clonic jerks of the eyelids and of the head, without falls. She received other anti‐seizure medications (ASMs) as levetiracetam (LEV), zonisamide (ZNS), and ethosuximide (ESM), with only a transient reduction in seizure frequency on ESM. She also had a ketogenic diet (KD) for three‐month, achieving ketosis, without any change in seizure frequency. The interictal electroencephalogram (EEG) at the age of five showed a slow background activity in wakefulness and a poor organized sleep as well as abnormal rhythms of alpha band and bursts of bi‐frontal poly‐spikes and poly‐spike–waves predominant on the left. Several absences were recorded with behavioral arrest and clonic jerks of the eyelids lasting around 5 s concomitant to generalized, predominant on anterior regions high amplitude spike waves at the frequency of around 2.5 Hz. Photo paroxysmal response was present at the age of six, without triggering absence seizures, but was not observed thereafter.
Metabolic tests were unremarkable. Genetic analysis for Angelman Syndrome, array‐CGH, and epilepsy gene panel including 250 epilepsy‐related genes were unrevealing.
At 6 years of age, she presented 15–20 atypical absences per day with up gaze, clonic eyelid jerks and atonic component. They lasted about 10 s and occurred in series of 3–4 seizures two to three times per day. Rufinamide (RFN) was added without efficacy on seizure frequency. Sleep was characterized by several diffuse poly‐spikes and waves predominant on the anterior and left regions. Photosensitivity testing and hyperpnea response were negative.
At 7 years of age, she presented 50 seizures per day, and she had a transient improvement after a vague nerve stimulation (VNS). The improvement was concomitantly on seizures, language, and behavior. Seizures were shorter, and series were less frequent with less seizures per series. She had an acute exacerbation 3 years after, and the VNS was switched off after various unsuccessful changes in the stimulation pattern. The interictal EEG during wakefulness showed a slow background activity with bilateral frontocentral and parieto‐temporal spikes predominating on the left. Atypical absence seizures were frequent (approximately 15 per hour) and were associated with generalized high‐amplitude spike‐and‐wave discharges at 2.5 Hz, lasting 2–20 s, beginning with a burst of generalized poly‐spikes lasting around 2 s (Figure 1A).
FIGURE 1.
Electroencephalographic (EEG) examinations and brain magnetic resonance imaging (MRI) performed in our patient. (A) EEG performed at 9 years and 10 months during drowsiness shows atypical absence starting with bi‐frontocentral spikes and poly‐spikes followed by a generalized spike–waves discharge at 3 Hz. (B) EEG performed during drowsiness at 14 years reveals atypical absence initiating with generalized poly‐spikes, predominant in bi‐frontocentral regions, lasting 2 s, followed by a generalized poly‐spike‐wave pattern at 3, 5 Hz, intermixed with fronto‐central poly‐spikes. (C) Density Spectral Array (DSA) from central electrodes (C3 and C4) shows nine absences, each lasting 1–2 min, recorded over 1 h. Note the poly‐spike component around 20 Hz on the DSA. (D) Brain MRI performed at 5 years (FLAIR‐weighted images) shows leukodystrophy pattern with symmetric, diffuse subcortical and periventricular white matter abnormalities, predominantly sub‐tentorial and affecting periventricular frontal and parietal regions.
At the age of 10, seizures occurred daily, lasting up 10 min and characterized by behavioral arrest with sudden atonic fall of the head and trunk. Falls occurred sporadically. Cannabidiol (CBD) was then added with a transient improvement on behavior and seizure frequency.
At the last examination, at 14 years of age, she experienced approximately 30 atypical absence seizures per day, clustered into 3–4 series of four seizures each. The atypical absences lasted 1–2 min. During the seizures, she exhibited a marked tonic up gaze, clonic jerks of the eyelids and eyebrows, and vertical oculoclonus. On the EEG, the absences began with generalized high‐amplitude poly‐spikes lasting 1–2 s, followed by high‐amplitude generalized rhythmic poly‐spike‐and‐wave discharges at 3.5 Hz. The poly‐spike‐and‐wave discharges were most abundant at the onset of the absence (Figure 1B). The interictal EEG was normal in the awake state. Density Spectral Array (DSA) performed from central electrodes (C3 and C4) showed nine absences, each lasting 1–2 min, recorded over 1 h (Figure 1C). The brain MRI showed symmetrical abnormalities in the subcortical and periventricular white matter (Figure 1D). She was treated with CBD, CLB, RFM, and ESM. She exhibited an unstable gait, good social interaction, and a moderate ID primarily affecting the language domain, with the ability to form short, simple sentences. She is able to dress and undress, and brush her teeth without help.
A genome sequencing study was performed and identified a de novo missense variant in the exon 4 of GATAD2B gene (c.545 T > C, p.Leu182Pro). This variant is not described as a polymorphism nor as a pathogenic variant (GnomAD, Decaf, Clinvar, HGMD‐Pro databases), and is predicted to be pathogenic by in silico software. 5 No other pathogenic/likely pathogenic variant has been identified by genome sequencing in this patient.
3.2. Literature review (Table 1)
Ninety‐four patients from 90 families (mean age 7.5 years [9 months‐35 years]) carrying heterozygous GATAD2B pathogenic or likely pathogenic variants were reported in the literature. 1 , 2 , 4 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 Eighty‐eight (88/94, 94%) were de novo, six (6%) where inherited from an unaffected parent carrying the variant at a low level of somatic mosaicism (<15% or reads in DNA extracted from leucocytes).
Almost all patients presented a moderate‐to‐severe intellectual disability (92/94, 98%). Considering patients aged more than 3 years, 16 of 85 (19%) were nonverbal. Only five of 85 (6%) were able to form short sentences and 64 of 85 (75%) pronounced only single words.
Autism spectrum disorder (ASD) was clinically diagnosed in nine of 94 (9%) of patients, and attention‐deficit hyperactivity disorder (ADHD) in four of 94 (4%). Psychiatric disorders are inconstantly described. Anxiety disorder was diagnosed in six of 94 (6%), irritability and aggressiveness in five of 94 (5%), and obsessive‐compulsive disorder (OCD) in two of 94 (2%) of probands.
Neurological examination showed childhood hypotonia in 69 of 94 (73%) and spasticity in two patients (2/94, 2%). Sixty patients (60/94, 64%) displayed macrocephaly (Standard Deviation ±6 on average). Considering patients aged more than 3 years, 42 of 85 (49%) presented wide‐based gait, seven of 85 (8%) fine motor and coordination disorders, and five of 85 (6%) were nonambulatory.
Facial dysmorphic features were described in 82% (77/94). The most common included prominent forehead (62/77, 80%), hypertelorism (49/77, 67%), and pointed chin (48/77, 62%).
Epilepsy was diagnosed in only 16 of 94 (17%) patients, with seizure onset during the first years of life (mean age 15 months, range age 1 month–5 years). Seizure semiology was variable, including focal (2/16, 12%), and primary generalized tonic–clonic seizures (3/16, 19%). Epilepsy was drug‐resistant in four of 16 (25%) of patients, whereas most probands achieved seizure control with one or few ASMs (12/16, 75%). EEG was reported abnormal in two of 16 (12%) of probands without further details.
Brain MRI showed abnormal findings in 46% (43/94). White matter signal abnormalities were the most common findings (19/43, 44%).
Cardiac abnormalities were detected in seven of 94 probands (7%). Aortic valve defects were the most common findings reported (4/7, 57%).
4. DISCUSSION
Ninety‐four patients carrying GATAD2B pathogenic or likely pathogenic variants are reported with a broad clinical spectrum encompassing intellectual disability, hypotonia, ophthalmological abnormalities, macrocephaly, dysmorphisms, brain RMI abnormalities, and other variable features such as epilepsy, psychiatric disorders, and cardiac defects. 1 , 4
We reported a patient carrying a novel likely pathogenic missense GATAD2B variant lying on the conserved region domain 1 (CR1). She presents a DEE characterized by drug‐resistant atypical absence seizures, which significantly affected her daily life. CBD and VNS reduced her seizure frequency and intensity transiently with concomitant behavior, attention, and language improvement. She presented a moderate ID mainly affecting language domain that improved over the years. She achieved a verbal communication with small sentences of few words.
Epilepsy is reported in 17% of patients carrying GATAD2B pathogenic variants although epilepsy characteristics are often lacking. Seizures reported are generalized tonic–clonic or focal often drug‐responsive. Epilepsy seems more frequent in patients with missense variants affecting one of the two highly conserved domain of the protein CR1 or CR2 and represents the only significant phenotype compared with patients carrying other types of GATAD2B mutations. 1 , 4 However, patients carrying missense mutations are too few to assert this correlation. 4
Atypical absence seizures are generalized seizures. They may be included, when occurring as the only seizures' type, in the spectrum of the generalized genetic epilepsies (GGE). Although genetic, GGE are often related to a polygenic etiology and only few are monogenic. 19 , 20 , 21 Atypical absences are characterized by non‐abrupt onset or cessation, a more prolonged duration (usually between 10 and 60 s). They can be observed in several epileptic syndromes such as Lennox–Gastaut Syndrome, developmental and epileptic encephalopathy with spike‐and‐wave activation in sleep (DEE/EE‐SWAS), and epilepsy with myoclonic atonic seizures (EMAtS) as well as in several specific syndromes such as: Glucose transporter 1 deficiency syndrome (Glut1DS), GABRG2, GABRG3, SLC6A1, CACNB4, SCN8A, and SYNGAP1, which display a greater probability of psychiatric and neuropsychological comorbidities. 22 GATAD2B pathogenic variants should be added to the monogenic causes of drug‐resistant atypical absences in DEE setting. However, further studies detailing GATAD2B‐related epilepsies are needed to support the association between GATAD2B variants and drug‐resistant atypical absences detected in our patient.
The most frequent radiological patterns detected in patients with GAND were a diffuse nonspecific white matter abnormalities and enlarged CSF spaces frequently associated with macrocephaly. These may be the expression in developing brain of abnormal cellular networking, proliferation and migration. 1 , 4
GATAD2B‐related phenotypes overlap with those reported with the mutations of other NuRD members, suggesting a shared pathogenesis affecting the NuRD complex functions. 1 Particularly, GATAD2B protein may act as a bridge that links methyl‐CpG‐binding domain (MBD) proteins and chromo‐domain helicase DNA‐binding (CHD) chromatin remodeling proteins through its CR1 and CR2 domains during brain development. 1 , 4 Interestingly, CHD chromatin remodeling proteins had a key role in brain development and were related to ASD, ID, and distinct epilepsy phenotypes including myoclonic epilepsies. 23
The GATAD2B haploinsufficiency during cortex genesis impairs migration, proliferation, and cellular cycle of distinct cell types, acting both directly and by modulating the expression of several target genes involved in neurodevelopment. 24 The resulting phenotype is therefore related to distinct gene–gene interactions and epigenetic factors that affect the transcriptional process. 1 , 4 , 24 In this setting, novel therapeutic‐targeted approaches would be essential to improve seizure control and improve the developmental outcome.
Our report expands the clinical and genetic spectrum related to GATAD2B variants, delineating an original etiology‐specific epilepsy phenotype as part of GAND. GATAD2B mutations may be associated with epilepsy with drug‐resistant atypical absence seizures and therefore should be included in the monogenic etiologies of GEEs.
CONFLICT OF INTEREST STATEMENT
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Supporting information
Table S1. The 16 articles reporting patients with pathogenic GATAD2B variants included in our review.
ACKNOWLEDGMENTS
RN is supported by the Chair Geen‐DS, institute Imagine, funded by FAMA fund hosted by Swiss Philanthropy Foundation by funds from France2030 program (ANR‐23‐RHUS‐0002), and by “Investissements d'avenir” ANR‐10‐IAHU‐01 program.
Scorrano G, Barcia G, Champ J, Courtin T, Boddaert N, Kaminska A, et al. GATAD2B‐related developmental and epileptic encephalopathy (DEE): Extending the epilepsy phenotype and a literature appraisal. Epilepsia Open. 2025;10:620–627. 10.1002/epi4.13133
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. The 16 articles reporting patients with pathogenic GATAD2B variants included in our review.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.