Table 1 Overview of main phenotypic features with severity score.

Individual	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15
Severity score^a	4	5	1	4	6	9	5	4	6	5	4	4	4	4	5
Age	11y	4y	18y	18y	12y	4y	3y 9mo	6y	2y	23y	2y	27y	20y	1y 4mo	10 mo
Sex	F	M	M	F	M	M	M	F	F	F	M	M	M	M	F
c.	96 C>G	421 T>A	455 C>T	532 A>T	533 C>A	536 C>T	539 T>C	539 T>C	539 T>C	539 T>C	539 T>C	538 A>G	538 A>G	538 A>G	539 T>A
p.	I32M	F141I	S152F	T178S	T178N	P179L	M180T	M180T	M180T	M180T	M180T	M180V	M180V	M180V	M180K
Inheritance	dn	dn	dn	dn	dn	dn	dn	dn	dn	dn	dn	dn	?	dn	dn
Birth size	N	N	N	N		N	N		N	N	N	N	N	N	N
Height	N	N	N	N	N	−3 SD	N		N	N	N	N	N	−2.6 SD	N
Head circumference	N	macroC	N	+5.1 SD	+2 SD	microC	+2 SD	macroC	+3.4 SD	+2.5 SD	+3.9 SD	+2 SD	+3 SD	+5.2 SD	N
DD/ID	ID++	ID+++	IQ 86	ID++	ID+++	ID+++	ID+++	ID++	ID++	ID++	ID++	ID++	ID++	DD	ID+++
Language delay	++	++	+	+	+++	+++	++		?	+	+	+	+	?	?
Age of walking	12mo	4y 9mo	15mo	2y	5y	none	3y		?	3y	2y	2y	13mo	16mo	?
Behavior	ASD, self-injurious	ADHD	ASD	OCD, anxious	ADHD, destructive					ASD, anxious		ASD	ASD
Hypotonia	yes	yes	no	yes	yes	yes	yes	yes	+++	++	+++	++	++	yes	+++
Feeding problems	no	reflux	no	no	yes	TPN			yes	mild	yes	no	yes	no	no
Epilepsy	++	N	no	no	no	++	no		no	no	no	no	no	no	yes
Corpus callosum	N	N	N		N	agenesis			hypoplastic	N	N	N	N	N	N
Other brain findings						ventricular megaly			delayed myelination	PVLM
Head/cranium	N	big head	N	frontal bossing	tall forehead	frontal bossing				tall forehead	frontal bossing	tall forehead	tall forehead	frontal bossing	frontal bossing
Ears/hearing	N	hypoplastic ears	N	N	microtia, hearing loss		hearing loss		microtia, hearing loss	N	N	N	N	N	N
Extremities/ spine	hyperm.	hyperm.	hyperm.	scoliosis	hyperm., scoliosis	scoliosis					hyperm.	hyperm., scoliosis	scoliosis
Heart	N	N	N			PDA			PDA	N	N

^athe severity score was calculated based on crude judgement of clinical severity: DD = 1 + 1-3 for ID (i.e. max=4), malformations = 1, corpus callosum hypoplasia/agenesis = 1, epilepsy = 1, short stature/SGA = 1, macro- or microcephaly = 1, other major findings (unspecified, based on overall impression of clinical severity) = 1. Language delay was scored from + to +++ when possible: + = mild, ++ = moderate, +++ = severe, based on the age of the individual and the clinical information provided. The scoring is crude but indicative. A “?” indicates “too early to know”. Similar scoring (+ mild, ++ moderate, +++ severe) was done of ID and hypotonia, when possible, otherwise “yes/no” or “ID” was noted.
Abbreviations: ADHD attention deficit-hyperactivity disorder, ASD autism spectrum disorder, DD developmental delay, dn de novo, hyperm. hypermobility, ID intellectual disability, macroC macrocephaly, microC microcephaly, mo months, N normal, OCD obsessive compulsive disorder, PDA persistent ductus arteriosus, PEG percutaneous endoscopic gastrotomy, PFO persistent foramen ovale, PVLM periventricular leukomalacia, SGA small for gestational age, TPN total parenteral nutrition, y years.

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