Table 1 Researcher-identified potential diagnoses (RIPDs) submitted by Clinical Genetics Group, Oxford (CGG) for patients with craniosynostosis (CRS) recruited to the 100,000 Genomes Project (100kGP)a.
Case | Researcher category (Box 2) | Panels applied in addition to CRS | Gene | cDNA change | Protein change | Tier | Exomiser rank | Inheritance | Gene green on original/updated panel? | Pathogenicity | Also identified by GE/GMC? | Currently identifiable by NHSE pipeline? |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
Tier 1, 2 or A variants | ||||||||||||
1 | N/A | 5 | MAN2B1 | c.[1830+1G>C];[2248C>T] | p.([?]); ([Arg750Trp]) | Tier 1; tier 2 | 2 | Recessive | Original | Pathogenic | Y | Y |
2 | N/A | 10 | 3.4 Mb Chr 6 del | − | − | Tier A | Unranked | De novo | Original | Pathogenic | Y | Y |
Monoallelic tier 3 variants | ||||||||||||
3 | N/A | 0 | KMT5B | c.557T>A | p.(Leu186*) | Tier 3 | 1 | De novo | No | Pathogenic | Y | Y |
4 | 2A | 1 | SMAD2 | c.1223T>C | p.(Leu408Pro) | Tier 3 | 2 | De novo | No | VUS | N/A | N/A |
5 | 2A | 0 | SMAD6 | c.40T>C | p.(Trp14Arg) | Tier 3 | 1 | De novo | Updated | Likely pathogenic | N | Y |
6 | 2A | 0 | CDK13 | c.2563G>C | p.(Asp855His) | Tier 3 | 2 | De novo | No | Likely pathogenic | N | Y |
7 | 2A | 7 | HNRNPK | c.1291G>T | p.(Glu431*) | Tier 3 | 1 | De novo | Updated | Pathogenic | N | Y |
8 | 2A | 1 | FBXO11 | c.2731_2732insGACA | p.(Thr911Argfs*5) | Tier 3 | 3 | De novo | Updated | Likely pathogenic | N | Y |
9 | 4A | 1 | SOX6 | c.242C>G | p.(Ser81*) | Tier 3 | 2 | De novo | No | Pathogenic | N | Y |
10 | 4C | 1 | SOX6 | c.277C>T | p.(Arg93*) | Tier 3 | 63 | Parents not available | No | Likely Pathogenic | N | N |
11 | 2A | 0 | BRWD3 | c.4012C>T | p.(Gln1338*) | Tier 3 | 1 | De novo | No | Pathogenic | N | Y |
12 | 2A | 1 | PTCH1 | c.290del | p.(Asn97Thrfs*20) | Tier 3 | 1 | De novo | No | Pathogenic | N | Y |
13 | 2A | 1 | ALX1 | c.541C>A | p.(Gln181Lys) | Tier 3 | 5 | De novo | No | VUS | N/A | N/A |
Untiered small variants | ||||||||||||
14 | 1B; 1B | 1 | MEGF8 | c.[4496G>A];[7766_7768del] | p.([Arg1499His]); ([Phe2589del]) | Both untiered | 96; unranked | Compound heterozygous | Original | Likely pathogenic/likely pathogenic | N | N |
15 | 1B; 1B | 3 | MMP21 | c.[671_684del];[775C>G] | p.([Val224Glyfs*29]); ([His259Asp]) | Untiered; tier 3 | Both unranked | Compound heterozygous | Original | Pathogenic/likely pathogenic | N | Y |
16 | 1A | 1 | ARID1B | c.3594delinsCCCCCA | p.(Gly1199Profs*14) | Untiered | Unranked | De novo | Original | Pathogenic | N | Y |
17 | 2A | 1 | TRAF7 | c.1885A>G | p.(Ser629Gly) | Untiered | 3 | De novo | Updated | Likely pathogenic | N | Y |
18 | 1E | 1 | TCF12 | c.1870C>T | p.(Leu624Phe) | Untiered | Unranked | De novo | Original | Pathogenic | N | Y |
19 | N/A | 3 | OGT | c.539A>G | p.(Tyr180Cys) | Untiered | 1 | De novo | Updated | Pathogenic | Y | Y |
Untiered copy-number and structural variants | ||||||||||||
20 | 3D | 0 | 13.4 Mb Chr 7 inv (TWIST1) | − | − | Untiered | Unranked | Dominant (proband, affected mother) | Original | Pathogenic | N | N |
21 | 3A | 1 | 314 kb Chr 19 del (ERF) | − | − | Untiered | Unranked | De novo (mosaic in unaffected father) | Original | Pathogenic | N | Y |
22 | 3D | 2 | 285 kb Chr 12 dup | − | − | Untiered | Unranked | Dominant (mosaic in affected father) | No | Likely pathogenic | N | N |
