Table 1.
Information on clinical phenotype and identified potentially pathogenic variants in novel VACTERL candidate genes.
| Family | Phenotypes | Gene | Pathway/ Complex |
Mode of transmission |
Nucleotide change |
State | Amino acid change |
Evolutionary conservationA |
PP2 SIFT MT CADD |
SNP ID |
gnomad B |
ACMG C |
Segregation |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 381_501 | A, C, R | B9D1 | Sonic hedgehog signaling, cilia organization | recessive | c.324G>A | het | p.(Val89Met) | D. rerio | 0.982 Del. D.C. 27.9 | rs777500443 | 0/2/251 074 | VUS (PM2, PP3) | Variant inherited from healthy father |
| B9D1 | Sonic hedgehog signaling, cilia organization | recessive | c.71_72del | het | p.(Pro24fs) | / | / | rs748661746 | 0/2/150 750 | Likely pathogenic (PVS1 ,PM2) | NA* | ||
| 794_ 501 |
V, A, R | FREM1 | Fraser complex | recessive | c.1408C>T | het | p.(Leu470Phe) | M. musculus | 0.359 Del. D.C. 23.1 | rs1418448401 | 0/0/245 792 | VUS (PM2, PP3) | Variant inherited from healthy father |
| FREM1 | Fraser complex | recessive | c.56C>T | het | p.(Ala19Val) | / | 0.001 Tol. Poly. 7.947 | rs368794455 | 0/6/232 056 | VUS (PM2) | Variant inherited from healthy mother | ||
| 358_ 501 |
V, R | ZNF157 | Kruppel family linking motifs, DNA transcription regulation | NA | c.764T>C | hemi | p.(Phe255Ser) | X. tropicalis | 0.999 Del. Poly. 10.51 | / | / | VUS (PM2, PP3) | Variant inherited from healthy mother |
|
GE_
052 |
V, R | ZNF157 | Kruppel family linking motifs, DNA transcription regulation | NA | c.667T>G | hemi | p.(Cys223Gly) | D. rerio | 0.999 Del. D.C. 15.48 | / | / | VUS (PM2, PP3) | Variant inherited from healthy mother |
| 395_ 501 |
V, A, R, L | SP8 | Wnt, Shh and Bmp signaling | NA | c.1510C>T | het | p.(Arg504Cys) | C. intestinalis | 0.988 Del. D.C. 31 | rs368503334 | 0/78/131 992 | VUS (PM2, PP3) | Variant inherited from healthy mother |
| SP8 | Wnt, Shh and Bmp signaling | NA | c.417C>G | het | p.(Phe139Leu) | D. rerio | 0.086 Tol. D.C. 17.23 | rs779330461 | 2/218/103 172 | VUS (PM2, PP3) | Variant inherited from healthy father | ||
| 605_ 501 |
V, A, C, R | ACOT9 | Fatty Acyl-CoA Biosynthesis | recessive | c.953G>A | hemi | p.(Arg318Gln) | D. rerio | 0.812 Del. D.C. 32 | / | / | VUS (PM2, PP3) | Variant inherited from healthy mother |
| 706_ 501 |
A, R, L | TTLL11 | Spindle and cilia microtubules organization | recessive | c.1540-8C>A | het | p.? | / | / | / | / | VUS (PM2) | Variant inherited from healthy mother |
| TTLL11 | Spindle and cilia microtubules organization | recessive | c.1298C>G | het | p.(Thr433Ser) | D. melanogaster | 0.997 Del. D.C. 25.9 | rs187536422 | 0/2/251 496 | VUS (PM2, PP3) | Variant inherited from healthy father |
Information on phenotype: A, anorectal malformation; C, cardiac malformation; L, limb anomalies; R, renal anomalies; V, vertebral malformation
CADD, Combined Annotated Dependent Depletion; D.C., disease-causing; Del., deleterious; del; deletion; fs, frameshift; gnomAD, Genome Aggregation Database; het, heterozygous; MT, Mutation Taster; NA, not available; PP2, PolyPhen 2; SIFT, Sorting intolerant from tolerant
Evolutionary conservation was assessed over 8 species: M. muscularis, Mus musculus; G. gallus, Gallus gallus; X. tropicalis, Xenopus tropicalis; D. rerio, Danio rerio; C. elegans, Caenorhabditis elegans; C. intestinalis, Ciona intestinalis; D. melanogaster, Drosphilia melanogaster; S. cerevisiae, Saccharomyces cerevisiae.
Variant frequencies listed for homozygous/ (if applicable) hemizygous/ heterozygous/ total alleles detected in the population.
ACMG American College of Medical Genetics guidelines classification as pathogenic, likely pathogenic, or variant of uncertain significance (VUS) (Richards et al., 2015).
no maternal DNA available; according to frequencies in gnomAD decided to be compound heterozygous.