Table 1.
Non-coding candidate variants and putative target genes
| Pedigree | CCDD | Sporadic vs familial | Isolated vs syndromic | Monoallelic vs biallelic variant(s) | Non-coding variant (hg38) | Peak Type | Nearest gene | Target gene | Distance to target (kb) | Reporter ID | Peak to gene r | Peak to gene FDR | gnomAD allele frequency | Predicted mechanism | SAD Z-score | Target gene loeufa | Target gene pHaplob | Target gene pTriploc | Non-coding Z-scored |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| S25 | CFEOM | S | I | M | chr10:129794079 TTGAG > T | D | EBF3 |
EBF3† (±DRS) |
170 | hs2776 | 0.24 | 2.90E-07 | 8.37E-05 | LoF | −11.77 | 0.15 | 1.00 | 1.00 | 3.10 |
| S176 | MGJW | F, AD | I | M | chr10:129884231 C > A | I | EBF3 | EBF3† (±DRS) | - | hs2775 | 0.29 | 3.89E-10 | 4.88E-05 | GoF | 0.11 | 0.15 | 1.00 | 1.00 | 3.74 |
| S95 | Ptosis | F, AD | Cr | M | chr10:129944464 G > C | I | EBF3 | EBF3† (±DRS) | - | hs2774 | 0.21 | 7.76E-06 | - | GoF | 0.98 | 0.15 | 1.00 | 1.00 | 5.14 |
| S12 | DRS | S | Ca | B(h) | chr11:72394626 C > G | I | CLPB | PHOX2A (+CFEOM) | 156 | - | 0.26 | 1.09E-08 | 1.41E-03 | GoF | 0.18 | 0.80 | 0.76 | 0.98 | 2.32 |
| S32 | Ptosis | F, AD | I | M | chr2:175005662 C > T†† | P | CHN1 | CHN1 (+DRS) | - | - | 0.48 | 1.31E-28 | 1.39E-04 | LoF | −0.38 | 0.57 | 0.41 | 0.72 | 2.59 |
| S251 | CFEOM/DRS | F, AD | I | M | chr2:175006051 GCTT > G†† | P | CHN1 | CHN1 (+DRS) | - | - | 0.48 | 1.31E-28 | - | GoF | 2.29 | 0.57 | 0.41 | 0.72 | 2.08 |
| S230 | DRS | S | I | M | chr20:40866929-40945626††† | D | TOP1 | MAFB (+DRS) | 256 |
hs2769 hs2770 |
0.23* | 1.19E-05* | - | - | - | 0.40 | 0.94 | 1.00 | 2.19* |
| S205 | CFP | S | I | B(ch) | chr5:51172762 T > A | D | ISL1 | ISL1 | 221 | hs1321 | 0.74 | 1.36E-86 | 2.26E-03 | LoF | −0.41 | 0.23 | 0.95 | 0.85 | −2.28 |
| S205 | CFP | S | I | B(ch) | chr5:51172961 T > G | D | ISL1 | ISL1 | 221 | hs1321 | 0.74 | 1.36E-86 | 2.33E-03 | LoF | −0.12 | 0.23 | 0.95 | 0.85 | −2.28 |
| S190 | DRS | S | I | B(ch) | chr22:27493955-27497536††,††† | D | MN1 | MN1 | 307 | hs2757 | - | - | 1.38E-04 | - | - | 0.48 | 0.99 | 0.92 | 0.29* |
| S238 | DRS | S DRS, F, AD SNHL | SNHL | B(ch) | chr22:27493955-27497536††,††† | D | MN1 | MN1 | 307 | hs2757 | - | - | 1.38E-04 | - | - | 0.48 | 0.99 | 0.92 | 0.29* |
| S191 | DRS | S | I | B(ch) | chr17:1455690 G > A†† | I | CRK | CRK | - | - | - | - | - | GoF | 0.44 | 0.34 | 0.97 | 1.00 | 0.30 |
| S191 | DRS | S | I | B(ch) | chr17:1456361 G > A†† | P | CRK | CRK | - | - | - | - | 1.51E-03 | LoF | −1.24 | 0.34 | 0.97 | 1.00 | - |
| S211 | DRS | S | I | B(ch) | chr17:1455565 C > T†† | I | CRK | CRK | - | - | - | - | 1.19E-04 | GoF | 0.49 | 0.34 | 0.97 | 1.00 | 0.30 |
| S211 | DRS | S | I | B(ch) | chr17:1456436 G C > G†† | P | CRK | CRK | - | - | - | - | 3.77E-04 | LoF | −12.28 | 0.34 | 0.97 | 1.00 | - |
| S211 | DRS | S | I | B(ch) | chr17:1456438 G > A†† | P | CRK | CRK | - | - | - | - | 3.77E-04 | LoF | −2.06 | 0.34 | 0.97 | 1.00 | - |
| WL | DRS | F, 2 sibs | I | M | chr17:48003752 A > C†† | D | CDK5RAP3 | CDK5RAP3 | 22 | hs2777 | 0.57 | 8.04E-43 | - | GoF | 4.31 | 0.97 | 0.24 | 0.54 | 1.94 |
| S174 | MBS | S | I | B(ch) | chr17:48003557 C > G†† | D | CDK5RAP3 | CDK5RAP3 | 22 | hs2777 | 0.57 | 8.04E-43 | 4.04E-03 | LoF | −0.15 | 0.97 | 0.24 | 0.54 | 1.94 |
| S174 | MBS | S | I | B(ch) | chr17:48003826 C > T†† | D | CDK5RAP3 | CDK5RAP3 | 22 | hs2777 | 0.57 | 8.04E-43 | 9.42E-04 | GoF | 1.69 | 0.97 | 0.24 | 0.54 | 1.94 |
| S156 | CFP | F, AD | I | M | chr3:128459417 G > C†† | D | DNAJB8 | GATA2 | 7 | - | 0.28 | 6.08E-10 | - | LoF | −4.88 | 0.34 | 0.98 | 0.87 | - |
| S180 | CFP | F, AD | I | M | chr3:128459454 A > G†† | D | DNAJB8 | GATA2 | 7 | - | 0.28 | 6.08E-10 | 3.95E-05 | GoF | 2.88 | 0.34 | 0.98 | 0.87 | - |
| S194 | CFP | F, AD | I | M | chr3:128459455 G > A†† | D | DNAJB8 | GATA2 | 7 | - | 0.28 | 6.08E-10 | - | GoF | 11.40 | 0.34 | 0.98 | 0.87 | - |
S sporadic, F familial, AD autosomal dominant inheritance pattern, SNHL sensorineural hearing loss, M monoallelic, B biallelic, h homozygous, ch compound het, ± denotes that reported individuals with variants in the gene have a syndromic phenotype and a subset also have the stated CCDD phenotype, + denotes an established CCDD gene for stated phenotype, I intronic, P promoter, D distal, LoF loss-of-function, GoF gain-of-function, I isolated, Cr craniofacial, Ca cardiac
aCoding loss-of-function intolerance—10.1038/s41586-020-2308-7
bCoding dosage sensitivity—10.1016/j.cell.2022.06.036
cNon-coding mutational constraint (1 kb windows)—10.1101/2022.03.20.485034
*mean value across deleted interval
†Multi-hit gene; ††Multi-hit peak; †††non-coding deletion