Table 1.

Clinical comparison of the previously described 19 individuals with severe clinical form of BRAT1-related neurodevelopmental disorder and the present study

References	Case ID	Gender/Cons	Origin	Mutation	HC	Hypertonia	Seizure onset	Seizure type	EEG pattern	MRI	Ex	Dev delay	Other
Puffenberger [7]	1	NK	Amish	Homozygous c.638_639insA p.Val214Glyfs*189	Poor head growth − 1.5/− 2.0 SD	+	Soon after birth	Focal jerks of the tongue, face, and arms	Bilateral medium–high voltage spikes over the temporal and central regions, frequent multifocal seizures, background slowing, and no posterior rhythm	Normal or mild hypoplasia of the frontal lobes	< 4 months	+	In utero episodic jerking, overlapping cranial sutures, apnea, bradycardia
	2	NK	Amish
	3	NK	Amish
Saunders [5]	1	F/+	Mexican	Homozygous c.453_454insATCTTCTC p.Leu152Ilefs*70	− 1.2 SD	+	1 day	NA	Focal epileptiform and sharp wave activity	Normal	NK	NA	Family history of infrequent seizures, bradycardia, patent foramen ovale, tricuspid regurgitation, peripheral pulmonary stenosis, bitemporal narrowing, micrognathia, flat nasal bridge, upslanted palpebral fissures, uplifted ear lobes, redundant helices, fifth finger clinodactyly, hyperreflexia
Saitsu [4]	1	F/−	Japanese	Compound Heterozygous c.176T>C p.Leu59Pro/c.962_963del p.Leu321Profs*81	Prog. Micr − 1.3 SD	+	7 days	Generalized tonic–clonic and myoclonic seizures of the limbs and face	Suppression-burst pattern	Progressive cerebral and cerebellar atrophy	21 months	+	Apnea, hyperreflexia,short webbed neck, micrognathia, optic atrophy
	2	F/−			Prog. Micr − 3.8 SD	+	1 day	Myoclonic, clonic, and tonic seizures	Suppression-burst pattern	Mild cerebral, cerebellar atrophy, and delayed myelination	3 months	+	Apnea, hyperreflexia, round face, thin lips, large ears pes equinovarus, optic atrophy
Straussberg [2]	1	F/+	Arabic	Homozygous c.1173delG p.Leu391fs	− 2.3 SD	+	1 day	Myoclonic	Sharp waves and bilateral spikes predominantly over the right hemisphere	Normal	5 months	+	Apnea, bradycardia, contractures, hyperreflexia, high frequency of fetal movements in utero
	2	M/+			1.05 SD	+	1 day	Myoclonic	Bilateral epileptic activity with bilateral discharges	Normal	6 months	NA	Apnea, bradycardia, contractures
Van de Pol [6]	1	M/+	Moroccan	Homozygous c.638_639insA p.Val214Glyfs*189	N	+	1 month	Tonic, clonic	Severely abnormal background, multifocal sharp waves, and frequent multifocal epileptic seizure activity	Progressive atrophy of the cerebral hemispheres, brainstem, and cerebellum	3.5 months	+	Hyperreflexia, dysmorphism; mild micrognathia, bilateral inguinal hernia, rocker bottom feet, prematurity
	2	F/+			Prog. Micr	+	1 month	Eye blinking, myoclonus	Continuous abnormal background pattern, multifocal seizure activity	Generalized atrophy	17 months	+	Apnea, high pitched cry
	3	M/+			Prog. Micr	+	1 month	Tonic, myoclonic	Burst-suppression pattern with long suppressions (10–15 s), multifocal negative sharp waves	NA	2 months	+	Dysmorphism; broad nasal bridge with prominent orbital ridges and glabella, prematurity
Horn [3]	2+	M/−	German	Compound Heterozygous c.638_639insA, p.Val214Glyfs*189 c.1134 + 1G>A	− 1.9 SD	+	1 day	Myoclonic	Diffuse slowing, bilateral spikes, and partly a burst-suppression pattern, epilepsia partialis continua	Normal	2 months	+	Apnea, in utero episodic jerking, hepatomegaly, atrial septal defect, contractures, round face, micrognathia
Smith [17]	1+	M/−	NA	Compound Heterozygous c.1857G>A; p.Trp619*/c.2125_2128delTTTG p.Phe709Thrfs*17	Prog. Micr − 4 SD	+	2 month	Facial myoclonus, focal dyscognitive, and secondarily generalized seizures	Bilateral multifocal epileptiform activity	Progressive cerebral and cerebellar atrophy, dysmyelination, and a region of focal encephalomalacia	15 months	+	Apnea, brachycephaly, thin lips, prominent ears, round nasal tip, bulbar dysfunction
Celik [16]	1	M/+	Turkish	Homozygous .2230_2237dupAACACTGC p.Ser747Thrfs*3	Prog. Micr − 3.7 SD	+	NK	Myoclonic seizures of the limbs and face	Background activity of – 6 Hz theta, bilateral frontotemporal sharp waves, and 8–10 Hz ictal rhythm during clinical seizures	Progressive cerebral and cerebellar atrophy and thinning of the corpus callosum	10 months	+	Apnea, in utero abnormal movements, hyperreflexia
Hegde [15]	1	F/+	Indian	Homozygous c.617T>A p.Leu206*	− 3.8 SD	+	3 days	Clonic seizures, eye blinks, and mouth movements, migrating partial epilepsy of infancy	Occasional generalized bursts of epileptiform activity with relatively well-preserved background activity, burst suppression pattern	Cortical and cerebellar atrophy with increased ventriculomegaly	4 months	+	Prominent forehead, bulbous nose, thin upper lip, retrognathia, camptodactyly
Szymanska [18]	1	F/−	NK	Homozygous c.1313_1314delAG p.Gln438fs	NA	+	1 day	Myoclonic	NA	Cerebral atrophy with a pronounced white matter volume loss, widening of the ventricles and the subarachnoid spaces, thinning of the corpus callosum	6 months	NA	Hypertelorism, epicanthal folds, low-set structure of the ear, high-arched palate
	2	M/-			− 3.2 SD	+	1 day	Myoclonic, tonic, clonic	Generalized and focal sharp and spike waves	Widened subarachnoid space	12 months	NA	Dysmorphism, recurrent infection, decreased cerebrospinal fluid homovalinic acid, pale optic discs
Skafi [13]	1	M/+	Lebanese	Homozygous c.638_639insA p.Val214Glyfs*189	NA	+	1 day	Myoclonic seizures of the limbs and face	Low-voltage background without epileptic discharges	Normal	3 months	NA	Apnea, hyperreflexia
Van Omeren [19]	1	F/−	Chinese	Homozygous c.1395G>C p.Thr465Thr	Prog. Micr − 3.5 SD	+	1 day	Myoclonic	Diffuse encephalopathy, with frequent ictal activity from multiple cortical areas	Mild thinning of the corpus callous and delayed myelination, pericerebral fluid excess due to atrophy	10 weeks	NA	Apnea
Present case	1	M/ +	Turkish	Homozygous c.1499-1G>T	+	–	1 day	Myoclonic, tonic, clonic Migrating focal seizure	Generalized epileptiform activity, migrating focal epileptiform activity, background deceleration	Atrophic corpus callosum, hypomyelinisation, brainstem, and cerebellar vermis hypoplasia	7.5 months	+	Overlapping cranial sutures, dysmorphism

Cons consanguinity, Dev developmental, EEG electroencephalogram, Ex exitus, F female, HC head circumference, M male, Micr microcephaly, MRI magnetic resonance imaging, NA not assessed, NK not known, Prog progressive, Ref reference, SD standard deviation, + represents the sibling with severe clinical form