Skip to main content

Table 1 Patient phenotype and variant summary

From: Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability

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

         
  1. 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
  2. aAge at examination is given in 5 year intervals in order to protect patient anonymity
  3. bPatient 51 also bears a de novo likely contributory CNV as detailed in the text, in addition to the SNVs given here