Table 2.
Identified MDRVs in the six recurrently affected chromatin genes in CTD cases.
| Gene | Variant ID | Chr | Position | Ref | Alt | AAF in GnomAD | Functional category and domain | cDNA and amino acid change, protein domain | ACMG | PhyloP | CADD | CCRS | Detailed cardiac phenoty pe | Sex | Ethnic group |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| EP400 | rs149894039 | 12 |
1319815 90 |
G | A | 1.76E-04 | D-Mis | c.1537 G > A;p.A513T | VUS | 9.49 | 25.5 | 93.9 | TOF | 2 | CEU |
| EP400 | rs149894039 | 12 |
1319815 90 |
G | A | 1.76E-04 | D-Mis | c.1537 G > A;p.A513T | VUS | 9.49 | 25.5 | 93.9 | TOF | 2 | CEU |
| KAT6A | chr8_419819 12 | 8 |
4198191 2 |
C | T | None | D-Mis; | c.752 G > A;p.R251Q | VUS | 4.75 | 28.7 | 82.3 | TOF | 2 | Hispanic |
| PHD domain | |||||||||||||||
| KAT6A | rs143207987 | 8 |
4204839 1 |
T | C | 8.02E-06 | D-Mis; Helix secondary domain | c.587 A > G;p.H196R | VUS | 7.56 | 24.3 | 81.4 | Aortic arch defect | 1 | CEU |
| KMT2C | chr7_152185 589 | 7 |
1521855 89 |
T | C | None | D-Mis; Helix secondary structure | c.5051 A > G; p.K1684R | VUS | 8 | 27.1 | 98.4 | RAA, VSD | 1 | CEU |
| KMT2C | rs145848316 | 7 |
1521855 87 |
C | A | None | D-Mis | c.5053 G > T; p.A1685S | VUS | 7.89 | 32 | 98.4 | TOF | 2 | CEU |
| KMT2D | chr12_49022 643 | 12 |
4902264 3 |
T | C | None | D-Mis; SET domain | c.16285 A > G;.p.T5429 | VUS | 6.27 | 15.6 | 90 | TOF | 2 | CEU |
| KMT2D | rs754358999 | 12 |
4904230 7 |
G | A | 3.21E-05 | D-Mis | c.5891 C > T;p.P1964L | VUS | 8.05 | 24.9 | 95.7 | TOF | 2 | CEU |
| NSD1 | chr5_177248 290 | 5 |
1772482 90 |
G | A | None | D-Mis | c.3800 G > A;p.G1267D | VUS | 8.6 | 28.5 | 99.7 | RAA | 2 | CEU |
| NSD1 | chr5_177280 761 | 5 |
1772807 61 |
A | G | 9.14E-06 | D-Mis; AWS domain | c.5012 A > G;p.Q1671R | VUS | 5.98 | 26.2 | 98.5 |
IAAB, ASD, VSD |
2 | CEU |
| PHF21A | chr11_45938 302 | 11 |
4593830 2 |
T | C | None | D-Mis | c.1322 A > G;p.H441R | VUS | 7.99 | 26.1 | 87.4 | RAA | 2 | African Descent |
| PHF21A | chr11_45948 887 | 11 |
4594888 7 |
T | C | None | D-Splicing |
NM_001101802:exon13:c.A1284G:p .R428R |
VUS | 6.56 | 12.3 | 85.9 | RAA | 1 | CEU |
Genes are listed alphabetically among the six chromatin genes. D-Mis Damaging missense variants, D-Splicing Damaging splicing variant, CADD Combined annotation- dependent depletion, CCRS Constrained coding regions, CEU Caucasian, TOF Tetralogy of Fallot, RAA Right sided aortic arch, IAAB Interrupted aortic arch type B, PHD The plant homeodomain, SET Su(var)3-9, Enhancer-of-zeste and Trithorax; AWS,Domain, Associated With SET; 1 denotes male and 2 female, in sex column; All MDRVs (most damaging rare variants) reside in Consensus coding sequence regions (CCDS). GnomAD v3.1.2 (CEU+Latino/Admixed +African/African American). Rs145848316 in KMT2C was also identified in one isolated ASD patient and one isolated VSD patient, see Table 1. None of the other genes were identified for isolated ASD and isolated VSD. ACMG classification is derived from Franklin Genoox (https://franklin.genoox.com/clinical-db/home), VUS Variant of unknown significance.