Table 1.
The major human syndromes associated with radiosensitivity and/or radiosusceptibility.
| Syndromes | Mutated Genes |
Major Defective Mechanism | Prevalence per 100,000 |
SF2 (%) |
Cancer Predisposition | Aging Neurodegeneration |
Immuno- Deficiency |
Subcellular Localization of the Protein |
|---|---|---|---|---|---|---|---|---|
| Ataxia telangiectasia | Homoz ATM mutations |
DSB signaling and repair |
~1 | 1–5 | Leukemia, Lymphoma | No | Yes | Nucleus Cytoplasm |
| Ligase IV syndrome |
Homoz LIG4 mutations |
NHEJ | Few cases | 2–6 | Leukemia, Lymphoma | No | Yes | Nucleus |
| Nijmegen’s syndrome | Homoz NBS1 mutations |
DSB signaling and repair |
~1 | 5–9 | Leukemia, Lymphoma | No | Yes | Nucleus |
| Hutchinson-Gilford Progeria syndrome |
Heteroz* LMNA mutations |
Nuclear membrane | 0.12–0.25 | 8–19 | No | Yes | No? | Inner nuclear membrane |
| Agamma-globulinemia Bruton’s disease |
X-linked homoz BTK mutations |
V(D)J recombination | 1.4–2.8 | 10 | No Some cases of colorectal cancer due to infections |
No | Yes | Nucleus Cytoplasm |
|
Hypogamma-globulinemia
Lig I deficiency |
compound
heteroz LIGI mutations |
NER | one case | 11 | No | No | Yes |
Nucleus
Golgi apparatus Vesicles |
| ICF syndrome |
Homoz, compound heteroz, DNMT3B mutations | DNA methylation | ~50 cases | 14 | No? | Yes? | Yes | Nucleus but also cytoplasm in mutated cells |
| Glutathione synthetase deficiency | most compound heteroz GSS mutations |
Glutathione cycle | ~70 cases ~0.1 |
14 | No | Cerebellar degeneration in some severe cases | No? | Nucleus |
| NBSLD Syndrome |
Homoz, compound heteroz RAD50 mutations |
Few cases | 15 | No? | Yes? | No | Nucleus | |
| ATLD Syndrome |
Homoz or compound heteroz MRE11 mutations |
Few cases | 15–30 | No | Yes? | No | Nucleus Cytoplasm |
|
| Cockayne’s syndrome | Homoz or compound heteroz CS mutations | NER/TCR | 0.4 | 15–30 | No | Yes | No | Nucleus |
| Xeroderma pigmentosum | Homoz or compound heteroz XP mutations | NER/TCR | 0.4 to 1 | 15–30 | Skin cancer | Yes | No | Nucleus only, except for XPD (both nucleus and cytoplasm) |
| Usher’s syndrome |
Homoz USH mutations |
3–5 | 16 | No | Yes? | No | Cytoplasm | |
| Huntington’s disease |
Heteroz (gain-of-function) HTT mutations |
DNA methylation | 4–7 | 19 | No | Yes | No | Nucleus Cytoplasm |
| Duchesne’s dystrophy | X-linked DMD mutations |
1–9 | 16–28 | No | Yes | No | Cytoplasm | |
| Fanconi Anemia |
Homoz or heteroz X-linked FANC (A to D) mutations | 1 | 15–40 | Leukemia, squamous cell carcinoma Breast cancer |
No | Yes | Nucleus only, except for FANCD both nucleus and cytoplasm |
|
| Bloom’s Syndrome |
Homoz or compound heteroz BLM mutations |
HR/TLS | 0.5–2 | 15–40 | leukemia, lymphoma | No | Yes | Nucleus Cytoplasm |
| Gorlin’s (NF2) syndrome |
Heteroz or de novo PTCH1 mutations |
1–9 | 12–30 | Non-melanoma skin cancer | No | No | Golgi apparatus Cytoplasm domains |
|
| Tuberous sclerosis Complex syndrome |
Heteroz TSC mutations | DSB signaling and repair |
4–10 | 24 | CMS and PMS tumors | No | No | Cytoplasm |
| Von Recklinghausen (NF1) syndrome |
Heteroz or de novo NF1 mutations |
DSB signaling and repair |
200–300 | 15–35 | CMS and PMS tumors | No | No | Nucleus Cytoplasm |
| Li-Fraumeni syndrome | Heteroz p53 mutations |
Cell cycle regulation | 4–10 | 20-50 | breast, brain, leukemia, sarcoma | No | No | Nucleus Cytoplasm |
| Gardner’s syndrome |
Heteroz APC mutations | Cell adhesion | 2.2–3.2 | 18–30 | Mainly colorectal cancer | No | No | Nucleus Golgi apparatus |
| Turcot’s syndrome |
Homoz, compound heteroz, heteroz MLH mutations |
MMR | ~150 cases | 21–30 | Mainly colorectal cancer | No | No | Nucleus |
| Hereditary retinoblastoma | Heteroz RB1 mutations |
Cell cycle regulation | 5–7 | 25–35 | Retinoblastoma, sarcoma, melanoma, lung and breast cancer | No | No | Nucleus but also cytoplasm in mutated cells |
| Hereditary breast/ovary cancer | Heteroz BRCA2 mutations |
HR | ~125 | 20–40 | Breast/ovary cancer | No | No | Nucleus Cytoplasm |
| Hereditary breast/ovary cancer | Heteroz BRCA1 mutations |
HR | ~333 | 30–50 | Breast/ovary cancer | No | No | Nucleus Cytoplasm |
| AT heterozygotes |
Heteroz ATM mutations |
DSB signaling and repair |
1000 | 20–55 | High risk of breast cancer | No | No | Nucleus Cytoplasm |
| Werner syndrome |
Homoz or compound heteroz WRN mutations | HR/TLS | 2.5–5 | 20–55 | some rare cancers | Yes | No | Nuclear Cytoplasm for some mutations |
| Rothmund-Thomson syndrome | Homoz or compound heteroz RecQL4mutations | HR/TLS | ~300 cases | 30–50 | osteosarcoma | Yes | No | Nucleus Cytoplasm |
| Severe combined immunodeficiency | Homoz or compound heteroz Cernnunos or Artemis mutations |
V(D)J recombination NHEJ |
~33 | 30–50 | Some rare lymphoma |
No | Yes | Nucleus |
| Down’s syndrome |
Chromosome 21 trisomy |
100–150 | 25 | High risk of ALL and AML | Yes | Yes | - | |
| Lynch’s syndrome |
Heteroz MLH1, MSH2/6, hPMS2 mutations | MMR | 100–125 | 30–50 | Mainly Colorectal cancer | No | No | Nucleus |
| Alzheimer’s disease |
2000–4000 | No? | Yes | No | - |
Abbreviations: homoz, homozygous; heteroz, heterozygous; APC, adenomatous polyposis coli; AT, ataxia telangiectasia; ATM, ataxia telangiectasia mutated; BLM, Bloom; BRCA1/2, breast cancer susceptibility gene 1/2; BTK, Bruton’s tyrosine kinase; CS, Cockayne syndrome; DNMT3B, DNA methyltransferase 3B; FANC, Fanconi anemia; GSS, glutathione synthetase; HR, homologous recombination; ICF, immunodeficiency–centromeric instability–facial anomalies. IR, ionizing radiation; Lig, ligase; MMR, mismatch repair; hMLH1, human DNA mismatch repair 1; MRE11, meiotic recombination 11; NBS, Nijmegen breakage syndrome; NER, nucleotide excision repair; NF1, neurofibromatosis type I; NHEJ, non-homologous end joining; PTCH1, patched 1 gene; RB; retinoblasoma; RecQ; recombinase Q; RecQL4; recombinase Q-like 4; SF2, surviving fraction at 2 Gy; TCR, transcription coupled repair; TLS, translesion synthesis; TSC, tuberous sclerosis complex. V(D)J, variability, diversity, joining; WRN, Werner. XLF, X-ray repair cross complementing 4-like factor; and XP, xeroderma pigmentosum.