Blatt1
		Supporting Information: Supporting Table S4: Detailed genotype and phenotype data on the study cohort
	General data
	Patient / family number	1	2	3	4	5a	5b	6a	6b	7a	7b	8	9	10	11	12	13	14	15a	15b
	Country of referral	France	Canada	Australia	Iran	Iran	Iran	Turkey	Turkey	Germany	Germany	Germany	Belgium	USA	Ireland	France	Ireland	Spain	New Zealand	New Zealand
	Published case (indicate reference)	No	No	No	No	No	No	No	No	No	No	No	No	No	No	No	No	No	No	No
	Mutated gene	PHGDH	PHGDH	PHGDH	PHGDH	PSAT1	PSAT1	PSAT1	PSAT1	PSAT1	PSAT1	PSAT1	PSAT1	PSAT1	PSAT1	PSAT1	PSAT1	PSAT1	PSAT1	PSAT1
	Nucelotide change(s)	c.160C>T(homo)	c.488G>A (homo) 	c.638C>T (homo; UPD1) 	c.704C>T (homo)	c.1A>G (presumed homo; hetero in parents)	c.1A>G (presumed homo; hetero in parents)	c.129T>G (homo)	Presumably c.129 T>G (homo) (similar phenotype as sibling 6a)	c.181C>T (hetero,mat) c.296C>T (hetero,pat)	c.181C>T (hetero,mat) c.296C>T (hetero,pat)	c.235G>T(homo) (hetero in both parents)	c.296C>T (homo)	c.296C>T(hetero) c.870-1G>T(hetero)	c.296C>T (hetero, mat) missing 2nd allele 	c.733T>C (presumed homo; hetero in parents)	c.463G>C (hetero)  c.870-1G>T (hetero) 	c.870-1G>T (presumed homo; hetero in parents)	c.955delA (homo)	c.955delA (homo)
	Predicted consenquences on RNA / protein level	p.(Arg54Cys)	p. (Arg163Gln)	p. (Thr213Met)	p.(Ala235Val)	p.?	p.?	p.(Ser43Arg)	Presumably, p.(Ser43Arg)	p.(Arg61Trp); p.(Ala99Val)	p.(Arg61Trp); p.(Ala99Val)	p.(Gly79Trp)	p. (Ala99Val)	p.(Ala99Val); Splicing	p. (Ala 99Val)	p.(Cys245Arg)	p. (Glu155Gln); splicing	splicing	p.(Arg319Aspfs*14)	p.(Arg319Aspfs*14)
	Mutation screening method	Targeted sequencing	Targeted sequencing	Targeted sequencing	Whole exome sequencing	Targeted sequencing	Targeted sequencing	Whole exome sequencing	No gene analysis in this patient	Whole exome sequencing	Targeted sequencing	Whole exome sequencing	Targeted sequencing	Targeted sequencing	Targeted sequencing	Targeted sequencing	Targeted sequencing	Targeted sequencing	Targeted sequencing	Targeted sequencing
	Gender	Female	Female	Female	Male	Female	Female	Male	Male	Female	Male	Female	Male	Male	Female	Male	Female	Female	Male	Male
	Parental consanguinity (specify)	Yes	None known	None	First cousins	First cousins	First cousins	First cousins	First cousins	None	None	2nd dgree cousins	3rd degree cousins	None	NA	2nd degree cousins	None	None	None known	None known
	Affected siblings	None	None	None	Possibly affected fetus in previous pregnancy	One, patient 5b	One, patient 5a	One, patient 6b	One, patient 6a	One, patient 7b	One, patient 7b	Probably affected male sibling	None	None	None	Probably affected male sibling	None	None	One, patient 15b	One, patient 15a
	Ethnic background	Caucasian	Pakistan	NA	Caucasian	Caucasian	Caucasian	Turkish	Turkish	Caucasian	Caucasian	Arab	Arab	NA	NA	Turkey	NA	Caucasian	Tuvalu	Tuvalu
	Pregnancy, birth, death
	Polyhydramnios	No	No	No	Not reported	No	No	No	No	No	NA	No	No	No	No	No	No	No	No	No
	Decreased fetal movements	No	Yes	No	Not reported	No	No	No	No	No	NA	Yes	Not reported	Not reported	Yes	Yes	Yes	Not reported	Yes	No
	Intrauterine growth restriction (IUGR)	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	NA	Yes	Yes	Yes	Yes	Yes	Yes	NA	Yes	Yes
	Gestational age at birth	26+6 weeks	39+2 weeks	40 weeks	33 weeks	40 weeks	40 weeks	36 w	35 w	32+2 weeks	15 weeks	26 weeks	36+5 weeks	37+2 weeks	39 weeks	32 weeks	38+5 weeks	35 weeks	31+6 weeks #	18+6 weeks
	Birth weight	379 g (-2.5 SD)	1988 g (-3.2 SD)	2540 g (-2.0 SD)	1179 g (-2.1 SD)	1900 g (-3.7 SD)	2200 g (-2.9 SD)	2500 g (-1.7 SD)	NA	820 g (-2.4 SD)	33 g	278 g (-3.2 SD)	1330 (-3.8 SD)	1371 g (-4.0 SD)	2120 g (-2.9 SD)	770 g (-2.6 SD)	1507 g (-4.6 SD)	NA	1690 g (-0.2 SD)	96.2 g
	Body length at birth	28 cm (-2.7 SD)	42.5 cm (-3.1 SD)	39 cm (-5.0 SD)	31 cm (-4.9 SD)	40 cm (-4.6 SD)	39 cm (-5.0 SD)	47 (-1.1 SD)	NA	33 cm (-3.3 SD)	9 cm	Crown-rump 15.,5 cm	33 cm (-6.2 SD)	38.6 cm (-4.8 SD)	NA	30 cm (-4.7 SD)	Crown-rump 25.3 cm, crown-heel 25.8	NA	43 cm (+0.5 SD)	17.8 cm
	OFC at birth	18 cm (-4.5 SD)	27.4 cm (-5.0 SD)	28.2 cm (-4.7 SD)	26 cm (-2.9 SD)	30 cm (-3.4 SD)	29 cm (-4.1 SD)	30 (-2.3 SD)	NA	24 cm (-3.4 SD)	NA		25 cm (-5.5 SD)	24.6 cm (-6.1 SD)	NA	20.5 cm (-6.0 SD)	26.4 cm (-5.4 SD)	NA	29 cm (-0.2 SD)	11.6 cm
	Intrauterine fetal death (IUFD) / termination of pregnancy (TOP)	TOP	No	No	IUFD	No	No	No	No	No	TOP	TOP	No	No	No	TOP but fetal distress 
announcing IUFD	No	IUFD (stillbirth at 35 weeks of gestation)	No	TOP
	Liveborn (indicate age of death)	No	Yes (died on first day)	Yes (died after 30 days)	No	Yes (died after 27 days)	Yes (died after 5 days)	Yes (alive at age 4 years)	Yes (died a age 6.5 years)	Yes (died at age 4 months)	No	No	Yes (died on first day)	Yes (died after 5 days)	Yes (died after 7 days)		Yes (died on first day)	No	Yes (died shortly after birth)	No
	Craniofacial
	Slanted forehead	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	NA	Yes	Yes	NA	Yes	Yes	Yes	Yes	Yes	Yes
	Short neck	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	NA	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
	Malformed ears	Yes	Yes	No	Yes	No	No	Yes	Yes	No	NA	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	No
	Low-set ears	Yes	Yes	Yes	No	Yes	Yes	Yes	No	Yes	NA	Yes	Yes	Yes	Yes	Mildly	Yes	Yes	No	No
	Round gaping mouth	Yes	Yes	No	Yes	No	No	Yes	No	No	NA	No	Yes	No	Yes	Yes	Yes	Yes	No	No
	Everted lips	Yes	No	No	Yes	No	No	Yes (lower lip)	No	No	NA	Yes	Yes	Yes	Yes	Yes (lower lip)	Yes	Yes	No	No
	Cleft lip and / or cleft palate	No	No	No	No	No	No	Cleft palate	Cleft palate	Cleft palate	No	No	No	No	No	No	Cleft palate	No	No / NA	Cleft palate
	Micro- / retrognathia	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	NA	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
	Other craniofacial abnormalities (please specify)	Short nose, anteverted nostrils	Hypoplastic malar areas, broad nose, bilateral epicanthic folds, hypertelorism					Epicanthus inversus, prominent glabella, 	Flattened nasal root, epicanthus inversus				Hypertelorism			Marked hypertelorism, flattened nose, hypoplastic nares, long philtrum, low-set cheeks		Facial edema, hypertelorism, downslanting palpebral fissures, small nose, anteverted nares
	Ocular
	Proptosis	No	Yes	Yes	Yes	NA	NA	Yes	Yes	No	NA	NA	Yes	No	NA	No	Yes	Yes, mild	No	No
	Shortened / everted eyelids	Yes	No	No	Yes	Yes	Yes	Yes	NA	No	NA	NA	Yes	No	Yes	No	Yes	Yes	No	No
	Cataracts	Yes (bilateral)	Yes	No	No	Yes	Yes	Yes	Yes	No	NA	NA	No	Yes	No	Yes	No	NA	NA	NA
	Other ocular abnormalities (please specify)	Irregular fibers of crystalline
with central calcification						Vision problems due to cataract	Vision problems due to cataract					One eyelid fused; at post mortem exam: persistent fetal vasculature retinal detachment, optic nerve hypoplasia		Microcornea	Absence of eyelids
	Central nervous system
	Microcephaly	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	NA	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
	Lissencephaly / abnormal gyration (specify)	Yes	Yes	Yes, some lissencephaly	Yes	NA	NA	Deep cortical sulcus	NA	No	NA	Yes, pachygyria	Yes	Yes	NA	Yes, simplified gyration 
with disorganisation of the cortex	yes	Not on antental ultrasound; post mortem not done	Not on antental ultrasound; post mortem not done	NA
	Cerebellar hypoplasia	Yes	Yes	Yes	No	NA	NA	No	NA	No	NA	aplasia vermis cerebelli	No	Yes	NA	Yes (no identifiable cerebellum)	Yes	Not on antental ultrasound; post mortem not done	Yes	Abnormal cerebellum on ultrasound prior to TOP
	Corpus callosum hypoplasia / agenesis	Yes	Yes	Yes, agenesis	Yes	NA	NA	Yes	NA	Yes, agenesis	NA	Yes, agenesis	Yes, agenesis	Yes, agenesis	NA	Yes, agenesis	No	Not on antental ultrasound; post mortem not done	Not on antental ultrasound; post mortem not done	Not on antenatal ultrasound
	Hydrocephalus / enlarged ventricles	yes (moderate)	enlarged ventricles	yes	no	NA	NA	No	NA	yes	NA	yes	enlarged ventricles	yes	NA	no	yes	Not on antental ultrasound; post mortem not done	Not on antental ultrasound; post mortem not done	Not on antenatal ultrasound
	Intracerebral calcifications	Yes	Yes	unknown	No	NA	NA	No	NA	No	NA	No	No	No	NA	no	no	Not on antental ultrasound; post mortem not done	Not on antental ultrasound; post mortem not done	NA
	Spina bifida	No	No	No	No	No	No	No	No	No	No	No	No	No	No	No	No	No	No	No
	Other CNS abnormalities (please specify)	Ganglionic prominence, polymicrogyria (sylvian fissure and fronto-parietal), immature cerebral cortex without lamination, white matter rarefaction with edema and microcavitation, some temporal nodular neuronal heterotopia in white matter, hypoplastic central gray nuclei, hypoplasia of the corticospinal tracts, cerebellar cortex not well differentiated, rudimentary dentate nucleus and vermis	Diffuse pachygyria with thinned, abnormally laminated neocortex; diffuse severe telencephalic white matter rarefaction/cavitation predominantly involving the subplate with periventricular cysts; widespread gliosis and aplasia of the corticospinal tracts; thalamus and basal ganglia small and gliotic: cerebellar hypoplasia with atrophy of the folia and depletion of Purkinje cell, external and internal granular layers in the neocerebellum with white matter rarefaction and Bergmann gliosis	Sub-ependymal pseudocyst				Linear signal increase in FLAIR images on ependymal and sulcal faces					Absence of septum pellucidum	Reduced number of anterior horn motor neurons at autopsy		Large meningeal capillary vessels, large vessels in the germinative zone which is sparse, dysplastic thalami			Dandy-Walker malformation
	CNS findings verified by imaging /autopsy	Autopsy	Autopsy		Autopsy	None	None	Brain MRI	None					Autopsy				Antenatal ultrasound	Antenatal ultrasound	Antenatal ultrasound
	Limbs / sekeltal
	Joint contractures	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	NA	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
	Swelling of hands	No	Yes	Yes	Yes	No	No	No	No	No	NA	Yes	Yes	No	Yes	No	Yes	Yes	Yes	No
	Finger syndactyly	No	No	No	Yes	No	No	No	No	No	NA		Yes	No	Yes	No	Yes	Not described, but the fingers are just minimal appendages in the edematous hands	No	No
	Swelling of feet	No	Yes	No	Yes	No	No	Yes	NA	No	NA		Yes	NA	Yes	No	Yes	Yes	Yes	No
	Toe syndactyly	No	No	No	Yes	No	No	No	No	No	NA		Yes	No	Yes	No	Yes	Not described, but the toes, like the fingers, are just minimal appendages in the edematous hands	No	No
	Rockerbottom feet	No	Yes	Yes	Yes	No	No	Yes	NA	No	NA	Yes	Yes	Yes	Yes	Yes	Yes (right)	Extreme malposition of feet	Yes	Yes
	Clubfeet	Pes varus	No	No	No	No	No	No	NA	No	NA		Yes	Yes	Yes	No	Yes (left)	Extreme malposition of feet	No	No
	Other skeletal abnormalities (please specify)	Distal arthrogryposis, adducted thumbs, thin overlapping fingers	Prominent heels, transverse palamar creases		Scoliosis			Clenched fists	Clenched fists	Preaxial hexadactyly on the right side	Pectus excavatum	Clinodactyly on both sides, hypoplastic thumbs	Sacral agenesis	Clenched fists		Short tubular bones, narrow thorax, small hole on the occipital bone, mild hypomineralisation of the skeleton		Swelling of all joints, especially the elbows, wrists, knees and ankles; short fingers and toes	Hypomineralised long bones on antenatal ultrasound
	Additional
	Ichthyosis	Yes	Yes	Scaling of skin	Yes	Yes	Yes	Yes, very mild	NA	No	NA	No	Yes	Yes	Yes	Yes	Yes	No	No	No
	Restrictive dermopathy	No	Yes	No	Yes	No	No	No	No	No	NA	No	NA	Yes	Yes	No	Yes	Yes	Yes	Tight facial skin
	Short umbilical cord	Yes, 18 cm	Yes	No	NA	No	No	NA	NA	No	NA	No	No	NA	NA	Not reported	Yes, 19 cm	NA	Not reported	Not reported
	Heart defect (specify)	No	No	No	No	No	No	No	No	No	No	No	Yes, VSD	No	NA	Yes, atrioventricular 
septal defect, dextrocardia,
hypoplastic right ventricle and pulmonary artery	Yes, biventricular hypertrophy	Not on antental ultrasound; post mortem not done	Not on antental ultrasound; post mortem not done	No
	Hypoplastic lungs	No	Yes, with incomplete minor fissure of right lung and major fissure of left lung	No	Yes	NA	NA	No	No	No	NA	No	Not reported	Yes	Yes	No	Yes	NA	not on antental ultrasound; post mortem not done	No
	Endocrine / metabolic abnormalities (specify)	No	No	No	No	NA	NA	His: 27,9 (41-125), Ser: 47,16 (69-187), Anserin: 0 (31-51), Isoleucin: 0 (33-97)	NA	No	NA	No	NA	No	NA	NA	Normal adrenal and thyroid	NA	NA	NA
	Renal abnormalities (specify)	No	No	Small kidneys: R 3.8cm, L 3.4cm <5th centile	NA	NA	NA	No	No	No	No	No	Enlarged bladder, pyelic dilation, megaureteres 	No	NA	Small kidneys (weight 
corresponding to 24 
weeks gestation)	No	Not on antental ultrasound; post mortem not done	One kidney small with multiple cysts; other kidney large with pyelectasis	Bilateral hydronephrosis on antenatal scan but not on postmortem
	Hypoplastic genitalia	Yes	External genitalia posteriorly displaced, small ovaries	No	Yes	No	No	Yes	NA	Yes	NA	No	Yes	Yes	No	No	No	No	Yes	No
	Ambiguous genitalia	No	No	No	No	No	No	No	NA	No	NA	No	Micropenis	No	No	No	Everted vagina and labia	Yes	Yes	No
	Other (please specify)	Wide anus, amyotrophy						No speech,  hirsuitism, inguinal hernia, seizures, feeding diffuculty, dystonic posture; last measurements (age 4): OFC 42.5 cm (-5.2 SD), weight 102 cm (-0.5 SD), length 15.5 kg (-0.6 SD)		Duodenal atresia, annular pancreas	Gut malformation, 	Prevertebral and cephalic edema of the skin	Hydrops (ascites, prefrontal edema and pleural effusion)			Total situs inversus, posteriorly-set anus, sacral dimple, severe hypoplasia of all skeletal muscles (including facial muscles) which are replaced by fat tissue	Everted anus	Generalized oedema; amyotrophy of limb muscles, more marked distally	Single umbilical artery

		Legend: IUFD, intrauterine fetal death; NA, not availabe / not assessed; OFC, occipito-frontal head circumference; SD, standard deviation; TOP, termination of pregnancy
		Comment: # Estimation of gestational age in P15a was based on fetal size at the first scan, which correlated with a gestational age of 21+4 weeks; it is therefore probably underestimated											z scores according to Fenton data