Table 2.

Clinical findings of individuals with de novo H3-3A and H3-3B variants.

Age and sex	Individual 1	Individual 2	Individual 3	Individual 4	Individual 5	Individual 6	Individual 7	Individual 8	Individual 9	Individual 10
	10 yo & Female	28 yo & Female	13 yo & Male	4.5 yo & Male	14 yo & Female	33 yo & Female	4yo & Female	12 yo & Male	5 yo & Male	8 yo & Female
Gene (Transcript)	H3-3A (NM_002107.6)				H3-3B (NM_005324.5)
Variant	c.166C>A (p.Q56K)	c.271G>C (p.G91R)	c.365C>T (p.P122L)	c.386G>A (p.R129H)	c.23C>T (p.A8V)	c.25C>T (p.R9C)	c.28A>G (p.K10E)	c.68C>A (p.T23K)	c.155T>A (p.I52N)	c.410_411del (p.*137Cysext*9)
Prenatal	Unremarkable, uneventful	IUGR	Unremarkable, uneventful	Unremarkable, uneventful	NR	Induced for postterm pregnancy	Decreased fetal movements	SGA	NR	IUGR
Birth	Respiratory distress and difficulty feeding	NR	Unremarkable	Prematurity	SGA	Hypotonia Apneic episodes Difficulty feeding	Hypotonia, axial Weak cry Difficulty feeding	SGA	SGA	Possible seizure activity Immature thermoregulation
Growth/Endocrine	Short stature FTT	Short stature	Short stature FTT	Short stature with GH deficiency (delayed bone age [−3 to −4 SD]) FTT	Short stature FTT	Short stature Hypothyroidism Type 1 DM	None	Advanced bone age Precocious puberty Growth plateau at 11 years old	NR	Short stature Advanced bone age Congenital hypothyroidism
Neurodevelopmental	GDD (gross & fine motor and speech) Happy demeanor Water affinity	GDD (gross motor and speech) ID Happy demeanor	GDD (gross motor and speech)	GDD (gross & fine motor and speech) Happy demeanor	GDD/ID, non-verbal	GDD/ID (motor and speech delays)	GDD	GDD/ID (Motor and speech delays)	GDD Speech delay Developmental regression Autism	GDD Motor delay Speech delay Happy demeanor Stereotypic flying of arms
Neurologic	Microcephaly Hypotonia Wide-based gait Mild spasticity in the lower extremities	Microcephaly Hypotonia Hypertonia of the lower extremities Seizures Drooling Wide-based gait	Microcephaly Hypotonia Seizures Drooling Ataxia	Relative macrocephaly Hypotonia (R>L) Gait abnormality	Microcephaly Hypotonia Craniosynostosis?	Seizures, generalized	Hypotonia	Gait abnormality	Microcephaly Hypotonia Ataxia Seizures	Microcephaly Hypotonia Gait abnormality
Brain MRI	Moderately diminished white matter in the anterior halves of both cerebral hemispheres along with hypomyelination accompanied by ventriculomegaly	NR	NR	Borderline Macrocephaly	Leukoencephalopathy	Normal	Normal	Cortical dysplasia Cerebellar hypoplasia Hypoplasia of the corpus callosum	Normal	NR
Dysmorphic features	Facial asymmetry Hypoplastic helix Long and upslanting palpebral fissures Prognathia Long, thin fingers with camptodactyly Fingertip pads	Brachycephaly Synophrys Hypotelorism, mild Midface hypoplasia Open mouth appearance with full lips and protruding lower teeth Small hands & feet	None	Facial asymmetry (R>L) Slightly low-set ears Long eyelashes Open mouth appearance Pointed chin Bilateral branchial remnant (s/p) (more prominent on the right) Fingertip pads Small hands & feet	Plagiocephaly Heavy eyebrows Deep set eyes Long eyelashes Down-slanting palpebral fissures Thin upper lips Hypodontia Hypertrichosis in the trunk Sparse hair on the scalp Camptodactyly of 4th and 5th fingers	Flat facial profile Triangular shaped face Depressed nasal bridge Thin upper lip Relative mandibular prognathism Mild clubbing in fingers	Dolichocephaly Bitemporal narrowing Sparse hair on bitemporal areas Smooth philtrum, mild Incomplete single palmar crease Tapered fingers	Low anterior hairline Narrow forehead Large ears Down-slanting palpebral fissures Bulbous tubular nose Smooth philtrum Persistence of primary teeth Widely spaced teeth Pointed chin Bilateral 5th finger clinodactyly and brachydactyly Bilaterally digitalized thumbs Short middle phalanges on his fingers Broad big toes Pes planus	NR	Prominent forehead Posteriorly rotated ears Prominent eyebrows Hemangioma over glabella Blue sclerae Down-slanting palpebral fissures Upturned nose Midface hypoplasia Thin upper lip Small mouth Micrognathia High arched palate
Visual	Esotropia	None	Strabismus	None	Retinal degeneration Dysplastic optic nerve	Strabismus	Nystagmus	Severe myopia (−18 to −20 diopter)	Astigmatism Blindness in the left eye	Esotropia
Musculoskeletal	Joint hypermobility Pes planus	Scoliosis	Joint hypermobility Pes planus	Mild asymmetry of the lower extremities (R>L) Pes planus, mild	Scoliosis	Scoliosis, thoracolumbar	NR	Joint contractures	Hypermobility	Scoliosis Hypermobility
Gastrointestinal	NR	Constipation	Constipation GERD	Unremarkable	NR	NR	Constipation	Constipation	Dysphagia Vomiting Congenial malformation of small bowel	NR
Cardiologic	None	None	None	Resolved pulmonary artery branch stenosis Resolved PACs	NR	NR	None	None	NR	Bicuspid aortic valve and partial fusion of aortic leaflets
Other clinical findings	NR	Teeth issues	Sleep dysregulation Reduced sweating Erythema multiforme	Delayed teeth eruption Chronic dysfunction of Eustachian tubes and adenoid hypertrophy	NR	NR	Sensorineural hearing loss, bilateral Laryngomalacia	Normal hearing	Recurrent otitis media Velvety and hyperextensible skin, patchy and soft hair	Shallow dental roots

yo years old, IUGR intrauterine growth retardation, NR not reported, SGA small for gestational age, FTT failure to thrive, SD standard deviation, DM diabetes mellitus, GDD global developmental delay, ID intellectual disability, R Right, L left, GERD gastroesophageal reflux disease, PAC premature atrial contractions.