Table 1 Overview on the molecular and major clinical findings in the 15 newly identified patients carrying pathogenic variants. For further details see supplementary patients descriptions (ACMG American College of Medical Genetics and Genomics [9]; VUS Variant of Unknown Significance; SDS standard deviation score; ND not determined; NA not available; gw gestational week; DD developmental delay; ad autosomal dominant, ar autosomal recessive; hom homozygous, het heterozygous, hem hemizygous, com het compound heterozygous, imp imprinted; pat paternal, mat maternal; *published by Hübner et al. [17], ** published by Meyer et al. [25, 26]; *** according to the ACMG guidelines, these variants should be classified as VUS. However, in this study they were classified as (likely) pathogenic, see Additional file 3: Table 3)

PLAG1

1

603026

F

36

1370 (−3.12)

39 (−3.12)

30.5 (−2.2)

1 7/12 years

7.4 (−3.0)

71 (−3.6)

45 (−2.07)

Yes

No

IGF2

2a

147470

F

37

1800 (−2.7)

45 (−1.87)

32 (−1.36)

1 10/12 years

7.4 (−3.62)

74 (−3.5)

44 (−3.75)

Yes

Yes

2b

F

37

1590 (−3.18)

43 (−2.71)

31 (−2.07)

NA

NA

NA

NA

Yes

Yes

HMGA2

3*

600698

M

39

2360 (−2.6)

47 (−2.13)

31 (−3.31)

3 8/12 years

10 (−3.93)

88 (−3.24)

NA

Yes

No

HMGA2

4a*

600698

F

39

1400 (−4.65)

36 (−6.86)

NA

3 years

6200 (−7.09)

70 (−6.73)

42.5 (−7.42)

Yes

Uncertain

4b*

M

38

1050 (−5.18)

NA

NA

1 1/12 years

4100 (−6.76)

57 (−6.19)

40 (−6.06)

Yes

Uncertain

IGF1R

5

147370

F

31

930 (−2.03)

37 (−1.45)

NA

1 11/12 years

6.12 (−5.0)

74 (−3.5)

39 (−9.79)

Yes

No

ORC1

6

601902

F

40

1435 (−4.88)

43 (−4.02)

30 (−3.84)

31 years

21 (−10.31)

137 (−4.7)

47.5 (−7.15)

No

No

OBSL1

7

610991

M

NA

NA

NA

NA

2 5/12 years

8.3 (−4.02)

71.5 (−5.69)

50 (−0.16)

Yes

Yes

MBTPS1

8**

603355

M

40

2400 (−2.78)

47 (−2.39)

35 (−0.46)

5 4/12 years

120 (-4.51)

98.5 (-3.19)

49 (−2.21)

No

No

FANCA

9

607139

F

35

1099 (−2.98)

38 (−3.0)

27.5 (−2.88)

3 3/12 years

10.28 (−3.23)

85 (−3.23)

44 (−5.35)

Yes

No

NF1

10

613113

M

25.5

620 (−1.33)

32 (−0.7)

22.5 (−1.11)

6 2/12 years

12.65 (−5.08)

105 (−2.86)

47.5 (−3.65)

Yes

No

FGD1

11

300546

M

40

2700 (−2.13)

48 (−1.99)

33 (−2.03)

13 3/12 years

38 (−1.26)

148.8 (−1.99)

52 (−2.11)

Yes

No

CNOT3

12**

604910

F

40

3200 (−0.65)

48 (−1.68)

35 (0.18)

NA

NA

NA

NA

No

No

KMT2C

13

606833

M

41

3.35 (−0.85)

53 (−0.04)

35 (−0.69)

13 3/12 years

25.6 (−3.5)

138 (−2.7)

51 (−2.82)

No

No

PTEN

14

601728

M

38

3700 (0.89)

56 (2.13)

36 (0.79)

10 5/12 years

39 (0.53)

141 (−0.35)

61 (5.29)

No

No

PTPN11

15

176876

M

NA

NA

NA

NA

15 11/12 years

44.5 (−2.37)

161.1 (−2.03)

NA

No

Yes

PLAG1

1

Yes

4/6

NM_002655.2:

c.599dup

Chr8:

g.56167147dup

p.(Arg201Profs*52)

No

ad, het

de-novo

no

pathogenic:

PVS1, PM2, PM6

SRS

180860

IGF2

2a

Yes

5/6

NM_001127598: c.381 T > G

Chr11:

g.2133610A > C

p.(Cys127Trp)

No

ad, het, imp

pat

sister

VUS***:

PM2, PP3, PP1

SRS

180860

2b

Yes

4/4

HMGA2

3*

Yes

4/6

NM_003483.4:

c.111 + 1G > T

Chr12:

g.65825382G > T

p.?

See Additional file 3: Table 3

ad, het

de-novo

no

pathogenic:

PVS1, PM6, PM2

SRS

180860

HMGA2

4a*

Yes

4/4

NM_003483.4:

c.239C > T

Chr12:

g.65838559C > T

p.(Pro80Leu)

See Additional file 3: Table 3

ar, hom

mat/pat

brother

VUS***:

PM2, PP3

SRS

180860

4b*

Yes

4/4

IGF1R

5

No

3/6

NM_000875:

c.3530G > A

Chr15:

g.98942995G > A

p.(Arg1177His)

See suppl. Information

ar/ad, het

Pat

NA

likely pathogenic:

PS2, PM2, PP3

resistance to IGF1

270450

ORC1

6

Yes

3/6

NM_004153.3:

c1996C > T

c.692del

Chr1:

g.52383437G > A

g.52861747del

p.(Arg666Trp)

p.(Pro231Glnfs*12)

rs201253919

rs1362231446

ar, com het

mat/pat

no

c.1996C > T: likely pathogenic:

PM2, PM3, PP3, PP5

c.692del: likely pathogenic:

PVS1, PM2

Meier-Gorlin syndrome 1

224690

OBSL1

7

Yes

4/6

NM_015311.2:

c.1382G > A

arr[hg19]2q35

(220300895_220596562) × 1

Chr2:

g.219567870C > T

p.(Trp461*)

whole gene deletion

No

ar, com he

NA

NA

pathogenic:

PVS1, PM2, PM3

3 M syndrome 2

612921

MBTPS1

8**

Yes

4/6

NM_003791.3:

c.1094A > G

Chr16:

g.84087398 T > C

p.(Asp365Gly)

rs1226321681

ar, hom

mat/pat

No

likely pathogenic:

PS3, PM2, PP3, PP5

Spondyloepiphyseal dysplasia

618392

FANCA

9

Yes

4/6

NM_000135.2:

c.2851C > T

c.2222 + 1G > T

Chr16:

g.89761950G > A

g.89770563:C > A

p.(Arg951Trp)

p.?

rs755546887, rs775488912

ar, com het

mat/NA

no

c.2851C > T: likely pathogenic:

PM2, PM3, PP5, PP3

c.2222 + 1G > T: likely pathogenic:

PVS1, PM2

Fanconi anemia, complementation group A

227650

NF1

10

Yes

3/5

NM_001042492:c.5488C > T

Chr17:

g.31327718C > T

p.(Arg1830Cys)

see suppl. Inform

ad, het

mat

no

likely pathogenic:

PS3, PM2, PP3, PP5

NF1

162200

FGD1

11

NR

2/5

NM_00463.2:

c.2761C > T

ChrX:

g.54446234G > A

p.(Arg921*)

rs869312743

XLR, hemi

de-novo

NA

likely pathogenic:

PS2, PM2

Aarskog-Skott syndrome

305400

CNOT3

12**

Yes

2/5

NM_014516.3:

c.658G > T

Chr19:

g.54145772G > T

p.(Glu220*)

No

ad, het

de-novo

two children

pathogenic:

PVS1, PS2, PM2, PP3

Developmental disorder, speech delay, autism, dysmorphic facies

618672

KMT2C

13

No

1/6

NM_170606.2:

c.11023C > T

Chr7:

g.151859639G > A

p.(Gln3675*)

No

ad, het

de-novo

no

pathogenic:

PVS1, PM2, PM6

Kleefstra syndrome 2

617768

PTEN

14

No

1/5

NM_000314.7:

c.518G > A

Chr10:

g.87952143G > A

p.(Arg173His)

rs121913294

ND

ND

no

likely pathogenic:

PM1, PM2, PP3, PP5

Macrocephaly/Autism

605309

PTPN11

15

No

2/2

NM_002834.4:

c.1508G > A

Chr12:

g.112489084G > A

p.(Gly503Glu)

rs397507546

ad

ND

ND

likely pathogenic:

PM1, PM2, PP3, PP5

Noonan?

163950