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Table 3 Damaging mosaics in CHD-relevant genes

From: EM-mosaic detects mosaic point mutations that contribute to congenital heart disease

ID

Gene

Variant class

Blood VAF

pLI

Episcore

HeartExp

Age (year)

Clinical phenotype

PCGC de novo LoF/Dmis variants in mosaic gene

Cardiac abnormalities

Extracardiac abnormalities

1-00761

FBN1

Dmis

0.24

1.00

98

93

1–5

Mitral stenosis

Dysmorphic features, subglottic stenosis, hypoplasic left mainstem bronchus, short stature

3

1-07004

TET3

Dmis

0.16

1.00

7

87

5–18

Subaortic stenosis

None

0

1-05662

SETD2

LoF

0.13

1.00

99

85

< 1

Aortic coarctation, mitral valve hypoplasia

None

0

1-00344

UBR5

splice

0.27

1.00

95

90

5–18

D-transposition of the great arteries, VSD, valvar and subvalvar pulmonary stenosis

None

0

1-03512

RFX3

LoF

0.09

1.00

100

46

< 1

Tetralogy of Fallot with pulmonary stenosis

None

0

1-06216

ITSN1

Dmis

0.21

1.00

98

86

< 1

ASD

Plagiocephaly, rib anomaly, single kidney, dysmorphic facial features

0

1-00363

QSER1

Dmis

0.06

1.00

94

79

1–5

Tetralogy of Fallot with pulmonary stenosis, VSD

inguinal hernia

0

1-13185

PKD1

Dmis

0.10

1.00

87

84

< 1

VSD, partially anomalous pulmonary venous return

Hemangioma

1

1-00192

GLYR1

Dmis

0.22

0.99

89

93

< 1

ASD, VSD, interrupted aortic arch, hypoplastic tricuspid valve, BAV

None

0

1-04046

FZD5

Dmis

0.09

0.99

89

48

< 1

Tetralogy of Fallot with pulmonary stenosis, VSD

None

0

1-06649

NOVA2

Dmis

0.15

0.95

75

56

< 1

Tetralogy of Fallot with pulmonary stenosis

None

0

1-05095

ISL1

LoF

0.07

0.90

97

25

1–5

ASD

None

0

1-06677

KCTD10

Dmis

0.16

0.84

75

91

5–18

Aortic coarctation, pulmonary valve stenosis

Dysmorphic facial features, hydrocephalus, pyloric stenosis, single kidney, imperforate/atretic anus

0

1-05447

HNRNPAB

Dmis

0.09

0.76

72

99

5–18

ASD, BAV, aortic coarctation

None

0

1-00021

QKI

LoF

0.13

0.76

94

97

< 1

Doublet outlet right ventricle, pulmonary stenosis, VSD

None

0

1-11871

FHOD3

Dmis

0.18

0.05

91

92

< 1

Tetralogy of Fallot with pulmonary atresia

Hypocalcemia, thrombocytopenia, lymphopenia

0

1-01458

HK2

Dmis

0.27

0.04

89

90

< 1

Hypoplastic left heart with aortic and mitral atresia, aortic coarctation

None

1

1-00669

PRKD3

splice

0.19

0.02

77

82

< 1

D-transposition of the great arteries, conal VSD, bilateral conus, interrupted aortic arch

None

0

1-00524

RNF20

LoF

0.10

0.00

55

83

18–25

Left-dominant complete atrioventricular canal

Heterotaxy with situs inversus totalis, asplenia, duodenal atresia

0

1-01851

SUCLA2

LoF

0.11

0.00

72

89

5–18

Balanced complete atrioventricular canal, aortic coarctation

None

0

1-03885

LZTR1

Dmis

0.20

0.00

31

84

5–18

Abnormal pulmonary vein draining into the right atrium

Left-sided/midline liver, asplenia, maltrotation

2

1-05011

KCTD20

Dmis

0.26

0.00

76

77

18–25

Transposition of the great arteries, tricuspid and pulmonary valve atresia

Left-sided/midline liver

1

1-00018

Figure 4

Dmis

0.19

0.00

49

70

5–18

BAV, mitral atresia, aortic coarctation, VSD, total anomalous pulmonary venous return

Nephritis

1

1-05661

SMAD9

Dmis

0.06

0.00

84

39

5–18

Common atrioventricular canal

None

0

1-09869

PIK3C2G

LoF

0.07*

0.00

73

28

5–18

Common atrioventricular canal, aortic stenosis, aortic arch hypoplasia, VSDs

Dysmorphic facial features, low-set ears, campomelic dysplasia

1

  1. There were 25 potentially pathogenic mosaic mutations based on known gene function and patient phenotype. Some of these probands have previously described rare LoF/Dmis variants, though none are likely pathogenic for CHD {Jin 2017}. Additionally, some genes were previously found to have LoF/Dmis variants among other individuals in this CHD cohort. Age ranges “A-B” denote A < =age < B. Abbreviations: ASD atrial septal defect, BAV bicuspid aortic valve, Dmis deleterious missense, episcore haploinsufficiency score (percentile rank) [29], Heart Exp heart expression percentile rank, LoF loss of function, pLI probability of loss-of-function intolerance, PCGC Pediatric Cardiac Genomics Consortium, VAF variant allele fraction, VSD ventricular septal defect. *VAF refers to CHD tissue WES