Table 1. Candidate causative variants in genes related to the HIF-1 pathway identified in our cohort of 94 probands with OD or MS.
Minor allele frequency (MAF) for each variant was accessed from the gnomAD version v2.1.1 on October 19, 2021. Inheritance was determined by Sanger sequencing from the parents’ germline samples, if available. Father—variant inherited from unaffected father; Mother—variant inherited from unaffected mother. NA–not available. Het–Heterozygous. bold—not present in gnomAD.
| ID | Disease | Gene mutated | Variant | Transcript | Genomic location (Build 37/hg19) | Zygosity | MAF | Inheritance | Malignancies | CADD score |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | MS | HIF1A | p.Val74Leu | NM_001243084:c.G220C | Chr14:62187212 | Het | 1.94e-3 | Mother |
No | 23.0 |
| 2 | OD | HIF1A | p.Pro239Leu | NM_001243084:c.C716T | Chr14:62194244 | Het | 0 | Mother |
No | 25.2 |
| 3 | OD |
HIF1A
|
p.Asp446Tyr | NM_001243084:c.G1336T | Chr14:62204819 | Het | 3.56e-3 | Mother |
No | 22.1 |
| 4 | OD | HIF1A | p.Arg655His | NM_001243084:c.G1964A | Chr14:62207705 | Het | 4.24e-5 | Father |
No | 14.22 |
| 5 | MS | HIF1A | p.Ala678Val | NM_001243084:c.C2033T | Chr14:62207774 | Het | 0 | Father |
No | 21.6 |
| 6 | OD |
HIF1A
|
p.Ser716Cys | NM_001243084: c.C2147G | Chr14: 62207888 | Het | 0 | Father |
Glioma | 1.008 |
|
IDH1
|
p.Arg132His | NM_005896:c.G395A | Chr2: 209113112 | Mosaic (Total number of reads – 54; VAF – 37%; Saliva sample) |
0 | de novo |
24.9 | |||
| 7 | MS | HIF1A | p.Glu481Lys | NM_001243084: c.G1441A | Chr14: 62204924 | Het | 0 | NA | No | 25.0 |
|
VHL
|
p.Pro25Leu | NM_000551: c.C74T | Chr3: 10183605 | Het | 2.99e-3 | 16.75 | ||||
| 8 | OD |
VHL
|
p.Pro25Leu | NM_000551: c.C74T | Chr3: 10183605 | Het | 2.99e-3 | Father | No | 16.75 |
| 9 | OD | VHL | p.Glu52Lys | NM_000551: c.G154A | Chr3: 10183685 | Het | 8.52e-5 | NA | No | 14.67 |
| IDH1 | p.Arg132His | NM_005896: c.G395A | Chr2: 209113112 | Mosaic (Total number of reads – 46; VAF – 32%; Enchondroma sample) |
0 | 24.9 | ||||
| 10 | OD |
VHL
|
p.Pro81Ser | NM_000551: c.C241T | Chr3: 10183772 | Het | 2.18e-4 | Father |
No | 23.0 |
| 11 | OD |
VHL
|
p.Ile180Val | NM_000551: c.A538G | Chr3: 10191545 | Het | 1.06e-5 | NA | No | 24.8 |
| 12 | MS | VHL | p.Arg210Trp | NM_000551: c.C628T | Chr3: 10191635 | Het | 3.59e-5 | NA | Nasopharyn-geal carcinoma undifferen-tiated type | 15.3 |
| 13 | OD | IDH1 | p.Arg132His | NM_005896: c.G395A | Chr2: 209113112 | Mosaic (Total number of reads – 76; VAF – 39%; Saliva |
0 | de novo | Glioma | 24.9 |
| 14 | OD | IDH1 | p.Ile189Val | NM_001282386: c.A565G | Chr2: 208243560 | Het | 3.68e-4 | Mother | No | 4.69 |
| 15 | OD | IDH2 | p.Thr435Met | NM_002168: c.C1304T | Chr15: 90627553 |
Het | 3.61e-3 | Father | No | 16.01 |
| 16 | OD | IDH2 | p.Thr435Met | NM_002168: c.C1304T | Chr15: 90627553 |
Het | 3.61e-3 | Mother - Het Father - Het |
No | 16.01 |
| 17 | OD | IDH2 | p.Asp225Asn | NM_002168: c.G673A | Chr15:90631596 | Het | 2.87e-4 | NA | No | 24.6 |
| 18 | OD | KDM4C | p.Tyr4Cys |
NM_001146696: c.A11G | Chr9: 6720959 |
Het | 1.08e-5 | Father | No | 3.376 |
| p.Ala774Thr | NM_001146695: c.G2320A | Chr9: 7049096 | Het | 1.77e-5 | Mother | 26.0 | ||||
| 19 | MS | KDM4C | p.Arg371Gln |
NM_001146695: c.G1112A | Chr9: 6981115 | Het | 2.29e-3 | Not in Mother, Father NA | Melanoma and chondrosarcoma | 3.622 |
| CDKN2A | p.Ala121Thr |
NM_058195: c.G361A | Chr9: 21971040 |
Het | 2.25e-4 | Mother, Father NA |
9.677 | |||
| 20 | MS | CDKN2A | p.Ala121Thr | NM_058195: c.G361A | Chr9: 21971040 |
Het | 2.25e-4 | Mother | No | 9.677 |
| 21 | MS | CDKN2A | p.Ala17Gly | NM_000077: c.C50G | Chr9: 21974777 |
Het | 0 | NA | No | 12.08 |