eTable 3. Patients with mutations in known disease genes or CNVs known to cause disease.

Patient	Consanguinity of parents	Other family members with similar symptoms	Phenotype (cardinal symptoms)	OMIM disease gene	Variant	Mutation nucleotide	Mutation protein	Inheritance	Associated disease	OMIM disease number
a) Mutations in known disease genes with concordant phenotype
1	No	No	Severe global developmental delay, regression, dysmorphism	del 15q11q13	CNV	chr.15: 23,684,690– 28,544,611x1		De novo	Angelman syndrome	# 105830
2	No	No	Severe global developmental delay, congenital cataract, microcephaly	COL4A1	Missense	c.1973C>A	p.Gly658Val	De novo	BSVD	# 607595
3	No	No	Mild global developmental delay, dystonia, gait disorder	SGCE	Nonsense	c.771_772delAT	p.Cys258Stop	De novo	DYT11	# 159900
4	No	No	Moderate global developmental delay, short stature, facial dysmorphism	ANKRD11	Nonsense	c.4886G>C	p.Ser1629Stop	De novo	KBG syndrome	# 148050
5	No	No	Severe global developmental delay, short stature, dysmorphism	KAT6A	Nonsense	c.1096G>A	p.Arg366Stop	De novo	MRD32	# 616268
6	No	No	Severe global developmental delay, spastic tetraplegic cerebral palsy, microcephaly	RNASEH2B	Missense	c.529G>A; c.529G>A	p.Ala177Thr; p.Ala177Thr	Autosomal recessive	AGS2	# 610181
7	Yes	No	Severe global developmental delay, regression, movement disorder, myelinization disorder	RNASEH2C	Missense	c.205G>A; c.205G>A	p.Arg69Trp; p.Arg69Trp	Autosomal recessive	AGS3	# 610329
8	No	No	Moderate global developmental delay, ataxia, stereotypes	MYT1L	Nonsense	c.223G>A	p.Arg75Stop	De novo	MRD39	# 616521
9	No	Yes	Severe global developmental delay, leukodystrophy, cerebellar hypoplasia	TREX1	Missense	c.290G>A; c.290G>A	p.Arg97His; p.Arg97His	Autosomal recessive	AGS1	# 225750
10	No	Yes	Mild global developmental delay, regression, hypotonia	TH	Missense	c.1273C>T; c.1096G>T	p.Glu425Lys; p.Leu366Met	Autosomal recessive	Segawa syndrome	# 605407
11	No	No	Severe global developmental delay, microcephaly, autism, stereotypes	MBD5	CNV	chr.2: 149,130,689–149, 227,038		De novo	MRD1	# 156200
12	No	No	Mild global developmental delay, neurodegenerative disorder	FA2H	Missense	c.1T>G	p.Met1Leu	Autosomal/ recessive	SPG35	# 612319
13	Yes	No	Moderate global developmental delay, regression, neuropathy, pyloric stenosis	ARSA	Missense	c.679G>C	p.Arg227Gly	Autosomal/ recessive	MLD	# 250100
b) Mutations in known disease genes with extension of phenotype
14	No	No	Severe global developmental delay, severe encephalopathy, dystonia	GLE1	Missense	c.1706G>A; c.1750C>T	p.Arg569His; p.Arg584Trp	Autosomal/ recessive	LCCS1, LAAHD	# 253310, # 611890
15	Yes	Yes	Severe global developmental delay, tapetoretinal degeneration, coordination disorder	RPIA	Missense	c.627G>C; c.627G>C	p.Trp209Cys; p.Trp209Cys	Autosomal/ recessive	RPIA deficiency	# 608611
16	No	No	Moderate delay in motor development, connective tissue weakness	IGHMBP2	Missense	c.745G>A; c.61C>T	p.Asp249Asn; p.Arg21Cys	Autosomal/ recessive	DSMA1, CMT2S	# 604320, # 616155
17	No	No	Severe global developmental delay, hypo‧tonia, hearing and vision deficiencies	CHD2	Missense	c.1854A>T	p.Glu618Asp	De novo	EEOC	# 615369
c) Mutations initially categorized as variants in candidate genes but reclassified as mutations in new disease genes in the course of the study
18	No	No	Severe global developmental delay, microcephaly, muscular hypotonia	CHAMP1	Frameshift	c.1865_1866delAC	p.Asp622 Glufs*7	De novo	MRD40	# 616579
19	No	No	Moderate global developmental delay, short stature, deafness	del Xq28 (SSR4, PLXNB3, SRPK3, IDH3G)	CNV	chr.X: 153,034,617– 153,060,208		De novo	CDG1Y	# 300934
20	Yes	No	Severe global developmental delay, cardiac abnormalities, muscular hypotonia, facial dysmorphism	SON	Frameshift	c.268delC	p.Ser90Valfs*59	De novo	ZTTK syndrome	# 617140
21	No	No	Severe global developmental delay, cardiac abnormalities, epilepsy, renal cyst	SON	Frameshift	c.4055delC	p.Pro1352Glnfs*14	De novo	ZTTK syndrome	# 617140

AGS2, Aicardi–Goutières syndrome 2; AGS3, Aicardi–Goutières syndrome 3; BSVD, brain small vessel disease with or without ocular anomalies; CDG1Y, ?congenital disorder of glycosylation type 1y; CMT2S, Charcot–Marie–Tooth disease, axonal, type 2S; CNV, copy number variations; DSMA1, spinal muscular atrophy, distal, autosomal recessive 1; DYT11, dystonia 11; EEOC, epileptic encephalopathy childhood onset; KBG syndrome, designation composed of the initials of the surnames of the first three patients described; LAAHD, lethal arthrogryposis with anterior horn cell disease; LCCS1, lethal congenital contracture syndrome 1; MLD, metachromatic leukodystrophy; MRD1, mental retardation, autosomal dominant 1; MRD32, mental retardation, autosomal dominant 32; MRD39, mental retardation, autosomal dominant 39; MRD40, mental retardation, autosomal dominant 40; OMIM, Online Mendelian Inheritance in Man; SPG35, spastic paraplegia, autosomal recessive 35; ZTTK syndrome, Zhu–Tokita–Takenouchi–Kim syndrome