Table 3.

Summary of the Clinical Features of Individuals with DNMs in GABRB2 (GenBank: NM_021911.2)

Individual	Gender	Age at Last Examination	DNM (Detection)	Cognitive and Behavioral Features	Epilepsy Diagnosis	Age at Seizure Onset	Seizure Types	AEDs	EEG	Brain MRI	Associated Neurological Features and Seizure Outcome
1242500	female	9.3 years	c.236T>C (p.Met79Thr) (cWESa)	GDD, severe ID	DEE	11 months	A or FIA	LEV	normal	arachnoid cyst	acquired microcephaly, axial hypotonia, spasticity, ataxia, minor dysmorphic traits (short perineum, tapered fingers, short broad great toes), seizures controlled with LEV
K.02591	female	10 years	c.373G>A (p.Asp125Asn) (WESb)	GDD, moderate ID	DEE	6 years	febrile, GTC	VPA	ND	normal	acquired microcephaly, no seizures (responded to VPA; off medication)
indvLB	female	1.5 years	c.878G>C (p.Arg293Pro) (WES)	GDD	no seizures	NA	NA	NA	normal	normal	severe psychomotor delay, generalized dyskinesia, dystonia, cortical visual impairment
CNSA01M	male	4 years	c.908A>G (p.Lys303Arg) (targeted gene panel)	GDD, severe ID	EOEE	1 day	Fo, MF, To	VPA, LEV, TPM, LTG	MF, slow background	diffuse T2 hypersignal in white matter at birth and 18 months	acquired microcephaly, neonatal feeding difficulties, nonambulation, hypotonia, spasticity, dystonia, rare seizures under TPM
T21213B	female	14 years, 6 months	c.911C>T (p.Ala304Val) (MIPS)	GDD, severe ID	DEE	4 years	M, A, At, non-convulsive SE	CLB, VGB, pred., TPM, HCT, VPA, LTG, LEV, CZP, SULTH	biF SW or sharp SW	normal	acquired microcephaly, nonambulation, hypotonia, intractable seizures
HSJ0753	female	4 years	c.730T>C (p.Tyr244His) (WGSc)	severe GDD	DEE	4 months	M, GTC, MSE	LEV, VPA, TPM, B6, DZP, CLB, PB, PHT, CBD, KD	biF SW, hyps., continuous diffuse SW	normal (at 9 days and at 1 year)	acquired microcephaly, nonambulation, axial hypotonia, spasticity, nystagmus, cortical visual impairment, intractable seizures
T23211	female	5 years, 1 month	c.730T>C (p.Tyr244His) (MIPS)	GDD, severe ID	DEE	<5 months	To, Fo, autonomic, M, SE	PB, LEV, CZP, P5P, B6, FOL, VGB, TPM, CBZ, NZP, OXBZ, VPA	MF (biF predominant), slow background	delay in myelination, reduction of white matter	congenital microcephaly, axial hypotonia, peripheral hypertonia, cortical visual impairment, choreoathetosis, dystonia, failure to thrive, intractable seizures
HA076	male	15 years, 8 months	c.830T>C (p.Leu277Ser) (WES)	GDD, severe ID	DEE	4 years, 8 months	M, At, A, GTC	VPA, TPM, CZP, CLB, LEV, LTG	slow, rhythmic notched slow waves	MF T2 hypersignal in white matter at 2 years, normal at 4 and 9 years	spasticity, poor coordination, broad-base gait, seizure control with LVT and LTG
G64518	female	10 years	c.830T>C (p.Leu277Ser) (WESb)	GDD, severe ID	DEE	2 years	GTC, A, febrile	VPA, LTG	high-amplitude rhythmic slow waves	mild increase in LVs at 2 years; normal at 3 years	acquired microcephaly, brisk reflexes, seizure control with LTG
31841	male	17 days	c.851C>A (p.Thr284Lys) (WES)	severe GDD	EME	7 days	M, To	PB, LEV, MDZ, biotin, FOL, B6	BS	normal	hypotonia, jitteriness, back arching, apneas, intractable seizures, deceased at age 17 days
3001866	female	21 months	c.946G>A (p.Val316Ile) (cWESa)	language delay	DEE	12 months	A or Fo, GTC	LEV, OXBZ, CNZ, ZNS	normal	normal	apneas, neuroendocrine cell hyperplasia of infancy, intractable seizures

Individual 1242500 was also previously identified with a pathogenic de novo mutation in CHAMP1 (Isidor et al.⁴²). Underlining indicates treatment with clinical response (decreased seizure frequency or severity), and italics indicates a negative response (aggravation of seizure frequency and/or severity). Abbreviations are as follows: NA, not applicable; ND, not done; cWES, clinical whole-exome sequencing; WGS, whole-genome sequencing; MIPS, molecular inversion probe sequencing; GDD, global developmental delay; ID, intellectual disability; DEE, developmental and epileptic encephalopathy; EOEE, early-onset epileptic encephalopathy; EME, early myoclonic encephalopathy; A, absence; At, atonic; GTC, generalized tonic-clonic; SE, status epilepticus; MSE, myoclonic status epilepticus; To, tonic; M, myoclonic; FIA, focal impaired awareness; Fo, focal; MF, multifocal; CZP, clonazepam; FOL, folinic acid; HCT, hydrocortisone; LTG, lamotrigine; MDZ, midazolam; NZP, nitrazepam; P5P, pyridoxal 5-phosphate; pred., prednisone; SULTH, sulthiam; AED, anti-epileptic therapy; LEV, levetiracetam; VPA, valproic acid; TPM, topiramate; CLB, clobazam; VGB, vigabatrin; B6, vitamin B6; DZP, diazepam; PB, phenobarbital; PHT, phenytoin; CBD, cannabidiol; KD, ketogenic diet; OXBZ, oxcarbazepine; ZNS, zonisamide; EEG, electroencephalography; biF, bi-frontal predominance; BS, burst suppression; SW, spike-wave; hyps., hypsarrhythmia; MRI, magnetic resonance imaging; WM, white-matter tracts; and LV, lateral ventricle.

^aBaylor College of Medicine and Miraca.

^bDDD study.

^cCENet.