Table 2 Unsolved cases with new candidate genes

From: Improving the diagnostic yield of exome- sequencing by predicting gene–phenotype associations using large-scale gene expression analysis

HPO terms used

Number of genes with candidate variant

Number of genes with Z ≥ 5

Candidate gene

Variants

CADD scores

GnomAD minor allele frequency

Supporting papers

Expression in relevant tissue

HP:0001644

215

5

OBSCN

NM_001098623.2:c.

[15037 C > T];

[20963delC]

24.8

25.2

8.0 × 10−5

1.7 × 10−3

30, 31

Yes

HP:0001644

226

3

OBSCN

NM_001098623.2:c.

[5545 C > T];

[22384 + 3

_22384 + 21del]

14.7

7.8

3.2 × 10−4

0

30, 31

Yes

HP:0008066

HP:0008064

359

3

FLG2

NM_001014342.2:c.

[632 C > G];[632 C > G]

35.0

1.1 × 10−5

49

Yes

HP:0001263

HP:0001249

HP:0000717

HP:0000708

HP:0002167

HP:0002360

HP:0000664

206

12

INO80

NM_017553.2:c.

[898C > T]

34

0

50, 51

Yes

HP:0001644

120a

2

MB

NM_00203377.1:c.

[214 G > A]

22.4

3.6 × 10−5

52

Yes

HP:0001644

120a

1

SYNPO2L b

NM_001114133.2:c.

[473 G > A]

24.1

5.4 × 10−4

53

Yes

HP:0001638

292

4

NRAP b

NM_001261463.1:c.

[4648 C > T]

20.4

8.7 × 10−4

54

Yes

HP:0004322

HP:0001249

381

10

CCNB2

NM_004701.3:c.

25-3_25delCAGG

24.5

0

55

Yes

HP:0003493

HP:0002583

246

6

LY75

NM_002349.2: c.

3476 C > T(;)

23 C > G

22.7

24.1

3.2 × 10−3

2.6 × 10−3

56

Yes

HP:0012649

HP:0002583

HP:0001890

318

8

AGAP2

NM_001122772.1:c.

421delC

27.2

0

57

Yes

  1. Note: In 10 out of 61 unsolved patients we identified likely causative genes that were previously unknown. For these genes we found literature that indicates these genes fit the phenotype of these patients or we gained functional evidence implicating their disease relevance. HP:0001644 = Dilated cardiomyopathy; HP:0008066 = Abnormal blistering of the skin; HP:0008064 = Ichthyosis; HP:0001263 = Global developmental delay; HP:0001249 = Intellectual disability; HP:0000717 = Autism; HP:0000708 = Behavioral abnormality; HP:0002167 = Neurological speech impairment; HP:0002360 = Sleep disturbance; HP:0000664 = Synophrys; HP:0001638 = Cardiomyopathy; HP:0004322 = Short stature; HP:0001249 = Intellectual disability; HP:0003493 = Antinuclear antibody positivity; HP:0002583 = Colitis; HP:0012649 = Increased inflammatory response; HP:0001890 = Autoimmune hemolytic anemia
  2. aThese variants were pre-filtered for family segregation
  3. bThe variants in these genes do not fully explain the phenotype but are likely contributing to the phenotype