Table 1 Summary of previous published cases of NSD2 haploinsufficiency

Age at last observation (years)

5

1

5.6 to 13.3

4

2.8

2

2 to 11

Genetic finding

12 patients with > 5 Mb deletion and 3 patient s with < 5 Mb deletion

191.5 kb deletion

1.9 Mb deletion

> 2 Mb deletion

1.9 Mb deletion

8 patients with > 5 Mb deletion and 13 patients with ≤5 Mb deletion

1.3 Mb deletion

109 kb deletion

60 to 377 kb deletion

IUGR

13/15

–

+

3/5

+

18/21

+

+

2/3

SGA

13/15

–

–

3/5

+

15/20

+

+

2/3

Postnatal growth retardation

15/15

+

+

5/5

+

16/21

+

+

1/3

Microcephaly

14/15

–

–

2/5

–

19/20

–

+

0/3

Craniofacial

15/15

+

+

5/5

+

20/21

+

+

3/3

High/broad forehead

N/A

+

+

1/5

–

17/18

–

+

3/3

Frontal bossing

N/A

–

+

0/5

+

0/21

–

N/A

Bitemporal narrowing

N/A

+

–

0/5

–

0/21

–

–

2/3

Prominent glabella

N/A

+

+

0/5

–

14/19

–

+

1/3

High arched eyebrows

N/A

+

–

0/5

–

0/21

–

+

1/3

Hypertelorism

N/A

+

+

0/5

–

16/19

–

+

3/3

Epicanthus

N/A

+

–

0/5

+

7/17

–

+

2/3

Prominent eyes

N/A

+

+

1/5

–

0/21

–

+

2/3

Downslanting palpebral fissures

N/A

–

–

1/5

–

0/21

+

+

0/3

Abnormal ears

N/A

+

+

1/5

+

17/20

–

+

2/3

Broad nasal bridge

N/A

+

–

4/5

+

13/19

+

+

3/3

Short philtrum

N/A

+

–

1/5

+

16/19

+

+

2/3

Downturned corners of the mouth

N/A

+

+

0/5

–

14/19

–

+

0/3

Micrognathia

N/A

+

–

0/5

–

15/20

+

+

3/3

Cleft lip/cleft palate

6/15

–

–

1/5

–

3/19

–

–

0/3

Hypotonia

15/15

–

+

0/5

+

13/19

+

–

2/3

Feeding difficulties

N/A

+

–

1/5

–

N/A

–

+

3/3

Seizures

14/15

–

+

2/5

+

15/21

+

–

0/3

Developmental delay

15/15

+

–

5/5

+

21/21

+

+

3/3

Abnormal behaviour

N/A

ADHD

–

N/A

N/A

N/A

N/A

ADHD, aggressiveness

ADHD 1/3

CNS structural abnormalities

N/A

N/A

–

Sacral dimple 4/4; delayed myelinisation 1/1

Sacral dimple

Sacral dimple 15/17

N/A

–

Distal ventral chordae 1/1

Hearing loss

N/A

+

–

N/A

N/A

N/A

N/A

Ophtalmological abnormalities

Iris coloboma 1/15

–

N/A

N/A

N/A

N/A

N/A

N/A

0/1

Cardiac features

9/15

–

–

N/A

–

ASD 2/19; AVSD 1/19; VSD 1/11; pulmonary stenosis 1/11

N/A

–

Left aortic arch, retroesophageal subclavian artery 1/3

Urinary tract malformations

Renal hypoplasia 3/15; hydronephrosis 3/15; renal fusion 1/15; hypospadias 5/15

–

–

Hypospadias 1/1; inguinal hernia 1/1

Bilateral pyelectasia

Left kidney duplication 1/18; VUR 8/18; hypospadias 8/18; right cryptorchidism 1/18; clitoridomegaly 1/18; ventrally spaced anus 1/8

N/A

–

VUR 1/3; left pyelectasia, cryptorchidism 1/3

Congenital diaphragmatic hernia

0/15

–

–

1/5

–

0/21

–

–

0/3

Skeletal abnormalities

N/A

Clinodactyly of V fingers, cutaneous syndactyly of I and III toes

–

Hyperkyphosis 2/5; small hands and feet 1/1

–

Scoliosis/hyperkyphosis 7/19; club feet 3/17

Small nails

–

0/3

Age at last observation (years)

1.3

Stillborn

2.8 to 5

3 to 7.2

3

2.2 to 5

12

10.5

Genetic finding

10 patients with > 2 Mb deletion

Pathogenic SNV

19 Mb deletion

Pathogenic SNV

68 to 166 kb deletion

Pathogenic SNV

Pathogenic SNV

Pathogenic SNV

Pathogenic SNV

18 patients with pathogenic SNV

IUGR

5/10

–

+

2/2

2/3

+

3/3

+

+

7/17

SGA

5/10

–

N/A

N/A

3/3

+

2/2

+

+

1/18

Postnatal growth retardation

10/10

+

N/A

2/2

3/3

+

2/3

+

+

16/17

Microcephaly

0/10

+

N/A

2/2

0/3

+

2/3

–

+

1/18

Craniofacial

10/10

+

N/A

2/2

3/3

+

3/3

+

+

17/17

High/broad forehead

10/10

+

N/A

0/2

3/3

–

1/3

–

–

8/17

Frontal bossing

0/10

–

N/A

0/2

N/A

–

0/3

–

–

2/17

Bitemporal narrowing

0/10

–

N/A

0/2

2/3

–

0/3

–

–

0/18

Prominent glabella

10/10

–

N/A

0/2

0/3

–

0/3

+

–

0/18

High arched eyebrows

10/10

–

N/A

1/2

3/3

+

0/3

+

+

2/17

Hypertelorism

10/10

+

N/A

1/2

2/3

+

0/3

+

+

6/17

Epicanthus

0/10

+

N/A

0/2

3/3

–

0/3

+

+

2/17

Prominent eyes

9/10

–

N/A

0/2

3/3

–

0/3

–

–

0/18

Downslanting palpebral fissures

0/10

–

N/A

0/2

0/3

–

0/3

–

–

0/18

Abnormal ears

2/10

+

N/A

2/2

2/3

+

1/3

–

+

8/17

Broad nasal bridge

10/10

+

N/A

2/2

2/3

+

1/3

+

–

4/17

Short philtrum

9/10

–

N/A

2/2

2/3

–

0/3

+

–

2/17

Downturned corners of the mouth

5/10

–

N/A

2/2

2/3

–

0/3

+

–

0/18

Micrognathia

4/10

–

N/A

2/2

1/3

–

0/3

+

+

3/17

Cleft lip/cleft palate

2/0

–

+

0/2

1/3

–

0/3

–

–

0/18

Hypotonia

9/10

+

N/A

2/2

2/3

+

3/3

+

–

12/17

Feeding difficulties

3/10

–

N/A

2/2

1/3

–

0/3

+

–

9/18

Seizures

8/10

–

N/A

0/2

0/3

–

0/3

–

–

2/17

Developmental delay

10/10

+

N/A

2/2

3/3

+

3/3

+

+

13/17

Abnormal behaviour

N/A

N/A

N/A

0/2

ADHD 1/3

Anxiety, hyperactivity, aggressiveness

Autism 1/1

N/A

N/A

Autism 7/17; ADHD 6/17; Aggressiveness 2/17; Anxiety 2/17

CNS structural abnormalities

N/A

N/A

N/A

0/2

Subependymal and intarathalamic hyperechogenic spots 1/3

Sacral dimple

Isolated 4 mm subependymal gray matter heterotopia 1/2

–

N/A

T2 hyperintensity and volume loss of the periatrial white matter 1/10; 8 mm pineal cyst, non-specific mild diffuse T2/FLAIR signal hyperintensity in the bilateral parietal and occipital white matter, small thoracic spinal cord syrinx 1/10; few small areas of gliosis in the frontal and periatrial area 1/10; thin corpus callosum, white matter lesions 1/10

Hearing loss

N/A

N/A

N/A

N/A

N/A

N/A

0/16

Ophtalmological abnormalities

N/A

N/A

N/A

0/2

Myopia 1/1

N/A

Myopia 1/1

N/A

N/A

Refraction defects 4/18; strabismus 2/18; bilateral keratoconus, retinitis pigmentosa, optic atrophy, corneal transplant 1/18

Cardiac features

ASD 3/8; pulmonary stenosis 2/8

N/A

N/A

0/2

Partial AVCD 1/2; mitral valve prolapse 1/2

N/A

N/A

–

–

Mild pulmonary artery stenosis 1/18; small PFO 1/18; interrupted aortic arch, VSD 1/18

Urinary tract malformations

1/10

Rotation of right kidney

N/A

0/2

0/3

N/A

Bilateral renal hypoplasia, CKD 1/2

–

N/A

Left renal agenesis 1/18; left hydronephrosis and hypospadias 1/18; bilateral cryptorchidism 1/18; congenital bilateral inguinal hernia 1/18

Congenital diaphragmatic hernia

0/10

–

+

0/2

0/3

–

0/3

–

–

0/18

Skeletal abnormalities

1/10

Clinodactyly of V fingers

N/A

0/2

Mild scoliosis, bilateral pes cavus, syndaktyly II-III toes 1/3

–

0/3

Clinodactyly of V fingers

–

8/18 (pectus excavatum, scapulae alatae, mild scoliosis, prominent knees, flat feet, broad forefeet, bilateral clinodactyly of the V toe 1/18; 11 ossified ribs and 6 non rib-bearing lumbar vertebrae 1/18; severe arthrosis of wrist and knee 1/18; clinodactyly of V fingers 3/18; bilateral cutaneous incomplete syndactyly of II and III toes 2/18; pes planus 2/18)