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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