Table 1.

Patient phenotype and variant summary

Patient #	Approx Age at Examinationa	Phenotype	Gene	Exonic function	AAChange	Chr	Co-ordinate (Hg19)	Other info	ACMG classification system	Comment	Other reports of same variant
43	Less than 5 years old	Feeding problems and failure to thrive, global developmental delay, Autism. Height 25%ile, weight -3SD, OFC 2-10%ile. CT/MRI-Dysgenesis of the corpus callosum.	ARID1B	Frame-shift single base deletion	NM_017519:c.1595delG:p.G532fs	6	157150413	het	PVS1, PS2, PM2 = Pathogenic	Sufficient to cause disease
58	Less than 5 years old	Developmental delay. Subtle growth difference involving whole left side. Height 75%ile, weight 25%ile, OFC 66th %ile. MRI- hemimegancephaly and hypertrophy on one side. Mild dilation of lateral ventricles, mildly smaller left hemisphere with suggestion of pachygyria near anterior temple lobes.	PHF6	Stop gain SNV	NM_001015877:c.C820T:p.R274a	X	133549136	het	PVS1, PS2, PM2, PP3 = pathogenic	Sufficient to cause disease	COSM144567, COSM1134629
59	Between 10 and 15 years old	Moderate developmental delay, facial dysmporphisms, seizure reported at 12 years. Enlarged labia. Self-abusive when angry. Height <25%ile, weight between 50th and 75th %ile. OFC 25th %ile. CT- mild ventriculomegaly.	SPRY4	Nonsynonymous SNV	NM_001127496:c.T508A:p.C170S	5	141694166	het	PS2, PM2, PP3 = Likely pathogenic	Possibly contributory to brain phenotype
			AP4E1	Nonsynonymous SNV	NM_001252127.1:c.T3140C:p.L1047P NM_007347.4:c.T3365C:p.L1122P	15	51294810	het	N/A	N/A
			AP4E1	Splice-donor SNV	NM_001252127.1:c.121 + 2 T > C NM_007347.4:c.346 + 2 T > C	15	51207770	het	N/A	N/A
45	Between 10 and 15 years old	Developmental delay and visual inattentiveness noted at 3 months. Athetoid movements with dystonic posturing present by 15 months and seizures noted by 2 years of age. At age four, a diagnosis of autism was suspected but could not be confirmed given the severe to profound ID. MRI: thin corpus callosum, increased ventricle and subarachnoid space size.	CACNB3	Nonsynonymous SNV	NM_001206915:c.G1289A:p.R430Q	12	49221639	het	PS2, PP3 = Uncertain significance	May play a role in the brain morphological phenotype
			SCN3A	Nonsynonymous SNV	NM_006922.3:c.T626C:p.L209P	2	166020196	het	N/A	Selected as candidate for epilepsy phenotype. Functional studies underway
51b	Between 15 and 20 years old	Significant intellectual disability. Gross motor delay. Seizuring. Scoliosis. Some hearing deficiency. Astigmatism and far-sightedness. Remarkable family history. Pregnancy complicated by possible oligohydramnios. Suctioned for meconium and physically stimulated. Placenta was calcified. MRI- asymmetrical lateral ventricles.	SQSTM1	Two base indel, causing a stop-gain	NM_003900: c.115_116delinsTA:p.A39a	5	179248051-179248052	het	PS2, PM2, PP3 = Likely pathogenic	Unsure of relative contribution of this variant versus others in the same child
			UPF1	Two base indel causing a mis-sense mutation	NM_002911: c.1576_1577delinsAA:p.A526N	19	18966765 - 18966766	het	PS2, PM2, PP3 = Likely pathogenic	Unsure of relative contribution of this variant versus others in the same child
42	Less than 5 years old.	Recurrent aspiration. Optic nerve dysfunction detected by absence of light reflex. Height, weight and OFC all at 25%ile. CT- absence of corpus callosum.	LRP2	Nonsynonymous SNV	NM_004525.2:c.G4351T:p.V1451F	2	170094756	het	N/A	N/A
			LRP2	Nonsynonymous SNV	NM_004525.2:c.A12725G:p.D4242G	2	170003335	het	N/A	N/A
41		CT- cerebellar atrophy
55		CT- mild dilation of the lateral ventricles

Abbreviations: ID Intellectual Disability, OFC occipito-frontal circumference, CT computerized tomography scan, MRI magnetic resonance imaging scan, PVS1 null variant in a gene where LoF is a known mechanism of disease, PS2 de novo in a patient with the disease and no family history, PM2 absent from controls in exome sequencing project, 1000 genomes project or exome aggregation consortium, PP3 multiple lines of computational evidence support a deleterious effect on the gene or gene product

^aAge at examination is given in 5 year intervals in order to protect patient anonymity

^bPatient 51 also bears a de novo likely contributory CNV as detailed in the text, in addition to the SNVs given here