Table 2.

Phenotypic characteristics of patients with de novo HECW2 missense variants

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6	Patient 7
Age	11 yo	9 yo	33 mos	33 mos	18 mos	3 yo	6 yo
Gender	Female	Male	Female	Female	Female	Male	Female
Mutation	c.3572G>A: p.Arg1191Gln	c.3572G>A: p.Arg1191Gln	c.3577T>G: p.Phe1193Val	c.3577T>G: p.Phe1193Val	c.3988C>T: p.Arg1330Trp	c.3988C>T: p.Arg1330Trp	c.4334A>G p.Glu1445Gly
Birth weight	3175 g	3941 g	2412 g	2155 g	3544 g	4196 g	2353 g
Current growth parameters	At 10 yo Wt=34.56 kg (36%ile) Ht=141 cm (35%ile)	Wt=25.4 kg (21%ile) Ht=131 cm (32%ile) OFC=52.8 cm (50%ile)	Wt=13.8 kg (60%ile) Ht=90 cm (23%ile) OFC=48 cm (39%ile)	Wt=12.8 kg (34%ile) Ht=87.9 cm (10%ile) OFC=50 cm (86%ile)	At 15 mos Wt=10.22 kg (59% ile) Ht=79.2 cm (88%ile) OFC=46 cm (65% ile)	At 23 mos Wt=12.56 kg (69%ile) Ht=90 cm (87%ile) OFC=48 cm (48%ile)	Wt=28.8 kg (<3%ile), Ht=104 cm (<3%ile), OFC=49.5 cm (<3%ile)
DD	+	+	+	+	+	+	+
ID	+ (Moderate)	+ (IQ=55)	NA	NA	NA	+	+
Autism	+	+	NA	NA	NA	NA	−
Age at sitting	9 mos	11–12 mos	Unable	Unable	Unable	Unable	Unable
Age at walking	3 yo	3 yo with braces	Unable	Unable	Unable	Unable	Unable
Age at talking	Non-verbal	2 yo; currently has ~15 words	Non-verbal	Non-verbal	One word at 17 mos	Non-verbal	Non-verbal
Hypotonia	+	+	+	+	+	+	+
Seizures	Generalised tonic clonic seizures at 5 yo (now seizure free)	EEG showed excessive slowing with abnormal burst discharges	Currently intractable tonic seizures	Currently intractable tonic seizures	−	Infantile spasms starting ~5 mos; has been a few months seizure free	EEG showed multifocal and generalised epileptiform and slow spike-wave discharges with diffuse background slowing
Abnormal behaviours	Hand flapping, self-injurious behaviours, aggressive behaviour, inappropriate laughter	Self-stimulatory behaviour	Rocking and flapping hand behaviours	Rocking and flapping hand behaviours	Repetitive hand movements, self-injurious behaviours	−	Self-stimulatory rocking, sucking on fingers
Other neurological problems	Wide-based gait, exercise intolerance	−	−	−	−	−	Choreiform movements
Visual problems	Strabismus	None	Strabismus, nystagmus with fevers	Strabismus, nystagmus with fevers	CVI	CVI	Optic atrophy and CVI
Brain MRI	Normal	Normal	Mild ventriculomegaly and increased extra-axial fluid	Mild ventriculomegaly and increased extra-axial fluid	Normal	Cerebral atrophy, thin corpus callosum	Progressive cerebral atrophy with mild cerebellar loss, atrophy of visual pathways, several small arachnoid cysts
GI problems	GERD, constipation	None	G-tube fed	G-tube fed	Requires burping regularly	G-tube fed	G-tube, gastroparesis, constipation
Dysmorphic features	Midface retrusion, thin vermillion upper lip	Flat nasal bridge, mild epicanthal folds, telecanthus, thick eyebrows, synophrys, short, upturned nose with bulbous nasal tip, midface hypoplasia, full lower lip, widely spaced teeth, tongue protrusion, thick supraorbital ridge, deep set eyes, mouth is wide and down turned, prominent central incisors	Deep set eyes, ptosis, prominent forehead	Deep set eyes, ptosis, prominent forehead	Slightly large ears, upturned nose with bulbous nasal tip	Sparse eyebrows, slightly depressed nasal bridge, upturned nasal tip	Hypotonic facies, highly arched palate
Other	−	Joint laxity in knees, ankles, pain insensitivity	Osteopenia, frequent waking at night	Osteopenia, frequent waking at night	−	Hyperglutaminaemia, scrotal hypoplasia, pectus excavatum	Gracile bones, mild osteopenia throughout with no definite dysplasia. Cardiomyopathy started prenatally, heart block, prolonged QT interval
Other genetic findings	−	−	−	−	−	439 Mb 15q11.2 duplication; de novo p. G184E SLC7A7 variant	Heterozygous G200V variant in EIF2B2 gene

%ile, percentile; −, absent; +, present; CVI, cortical visual impairment; GERD, gastro-oesophageal reflux disease; GI, gastrointestinal; G-tube, gastrostomy tube; Ht, height; ID, intellectual disability; mos, months old; NA, not available; OFC, occipital frontal circumference; Wt, weight; yo, years old.