Table 1

Clinical phenotypes

	Phenotype	Patient 1 (proband)	Patient 2 (father)	Patient 3 (paternal uncle)	Patient 4	Patient 5	Patient 6
Background	TRIO Mutation Coding change Protein change Exon Domain affected	Frameshift c.4466delA pGln1489Argfs*11 Exon 30 DH1	Frameshift c.4466delA pGln1489Argfs*11 Exon 30 DH1	Frameshift c.4466delA pGln1489Argfs*11 Exon 30 DH1	Missense c.4283 G>A p.Arg1428Gln Exon 28 DH1	Missense c.4381 C>A p.Pro1461Thr Exon 29 DH1	Missense c.3239 A>T p.Asn1080Ile Exon 19 Spectrin repeat
	MAF	Novel	Novel	Novel	Novel	Novel	Novel
	Inheritance	Inherited	Inherited	Inherited	AD de novo	AD de novo	AD de novo
	Sex	F	M	M	F	F	F
	Gestational age (weeks)	38	−	−	41	38	40
Development	Age at last assessment	17 months	36 years	10 years	16 years	8 years	9 years
Early milestones	First Smile	NR	NR	NR	8 weeks	36 weeks	NR
	Sitting unsupported	9 months	NR	NR	10 months	11 months	11 months
	Walking unaided	17 months	NR	NR	22 months	2.5–3 years	4–5 years
	First words	17 months	NR	NR	Unknown	4–5 years	Unknown
Current developmental level	General	Mild developmental delay	Mild learning difficulties attended special school	Mild developmental delay	Global developmental delay	Global developmental delay	Global developmental delay
Current developmental level	Language	Mild delay in expression and comprehension		Learning difficulties	Unable to read or write but very talkative		Non-verbal (Makaton)
Growth	Height	70 cm (<0.4th)	167 cm (9th)	126 cm (2nd)	159.4 cm (25th)	121.2 cm (9th)	121.6 cm (2nd)
	Weight	7.9 kg (<0.4th)	69.9 kg (50th^–75th)	20.5 kg (<0.4th)	41.1 kg (0.4th)	21.2 kg (9th)	20.2 kg (2nd)
	Occipital frontal circumference	42 cm (-5sd)	52 cm (-3sd)	48 cm (-5sd)	48 cm (-5sd)	47 cm (-5sd)	54.3 cm (75th)
Neurological	Stereotypies Aggression Poor attention Other	− − + −	NR	NR	+ + − Obsessive compulsive traits	− − + ADHD disrupted sleep	+ + − −
Neurological	Other	−	−	−	Pain insensitivity, urinary incontinence	−	Seizures (nocturnal tonic–clonic), gait ataxia
Gastrointestinal	Infantile feeding difficulties	+	NR	NR	−	+	+
Gastrointestinal	Other	Dietician input			Constipation		Previous gastrostomy
Skeletal	Digits	Short tapering fingers with swelling of PIP joints fifth finger cleinodactyly	Short tapering fingers with swelling of PIP joints and shortening of the metacarpals and phalanges	Short tapering fingers with swelling of PIP joints, fifth finger cleinodactyly, 2/3 left-sided toe syndactyly	Short tapering fingers with swelling of PIP joints, fifth finger cleinodactyly, 2/3 left-sided toe syndactyly	2/3 toe syndactyly and almost absent fifth toe nail	−
Skeletal	Spine	Rotational scoliosis, right radial aplasia and rudimentary thumb and absent metacarpal, no radial synostosis	Minor bony abnormalities of the low dorsal vertebrae with rotational scoliosis of the thoracolumbar spine	−	−-	−	Thoracolumbar scoliosis
Additional	Facial	Short nose, long philtrum, thin upper lip, epicanthic folds, synophrys	Straight nose, small jaw, pointed features, low anterior hairline, asymmetry	Straight nose, small jaw, low anterior hairline with frontal upsweep of hair, pointed features, asymmetry	Congenital ptosis, upslanting palpebral fissures, large fleshy ears, synophrys	Flat nasal bridge, synophrys	Plagiocephaly, Angelman-like facies, asymmetry
	Dental	NR	Dental delay	Dental delay	Dental overcrowding	NR	NR
	Other	2 VSDs and PFO, maternal Type 2 DM	NR	Asymptomatic ventricular ectopic beats with RBBB	Good musical memory	Strabismus, perforated ear drum	NR
	Additional variants	15q11.2 microdeletion	15q11.2 microdeletion	KCNJ2 (p.T75M) 15q11.2 microdeletion	−	−	−

−, absent; +, present; AD, autosomal dominant; ADHD, attention-deficit hyperactivity disorder; DM, diabetes mellitus; F, female; M, male; NR, not recorded; PFO, patent foramen ovale; PIP, proximal interphalangeal; RBBB, right bundle branch block; VSD, ventricle septal defect.