| Molecular subtype / lesion | Mechanism / genes affected | Approx. frequency among BWSp | Tumor risk estimates | Mosaicism / tissue-testing implications | Surveillance implications |
|---|---|---:|---|---|---|
| **IC1 gain of methylation (IC1 GOM; H19/IGF2:IG-DMR hypermethylation)** | Increased methylation at telomeric imprinting control region 1 causes **increased paternal-like IGF2 expression** and **reduced H19**; growth-promoting state strongly linked to Wilms tumor predisposition (pqac-00000034, pqac-00000041) | ~5% (pqac-00000005, pqac-00000042) | **Highest subgroup risk**: overall tumor risk **28.1% / 28%**; **Wilms tumor 24%**; neuroblastoma **0.7%**; pancreatoblastoma **0.7%** (pqac-00000005, pqac-00000001, pqac-00000042) | BWSp is often mosaic; blood epitype may not match kidney/tumor tissue. Some WT have isolated IC1 GOM without broader LOH, so negative blood testing does not fully exclude tissue-restricted disease (pqac-00000019, pqac-00000041) | Exceeds AACR **1%** threshold. Current practice update supports **renal ultrasound every 3 months from birth/diagnosis to age 7 years**; because BWSp also carries HB risk overall, many programs use **complete abdominal ultrasound every 3 months until age 3 years**, then renal ultrasound to age 7 (pqac-00000000, pqac-00000045, pqac-00000052) |
| **IC2 loss of methylation (IC2 LOM; KCNQ1OT1:TSS-DMR hypomethylation)** | Maternal IC2 hypomethylation permits **biallelic KCNQ1OT1** expression and **reduced CDKN1C** expression; associated with reduced growth suppression and classic BWSp features such as macroglossia/midline defects (pqac-00000039, pqac-00000034, pqac-00000042) | ~50% (pqac-00000005, pqac-00000042) | **Lower-risk subgroup**: overall tumor risk **2.6%**; hepatoblastoma **0.7%**; rhabdomyosarcoma **0.5%**; neuroblastoma **0.5%**; thyroid cancer **0.3%**; Wilms tumor **0.2%**; melanoma **0.1%**. Pooled cohort also showed hepatoblastoma in IC2 subgroup and very low WT risk (pqac-00000005, pqac-00000001, pqac-00000042) | Blood testing can miss mosaic 11p15 defects; additional tissues (buccal swab, skin/affected tissue) may be informative in clinically suspected but blood-negative cases. Tissue discordance is a known limitation for genotype–phenotype and risk assignment (pqac-00000013, pqac-00000014, pqac-00000019) | Still exceeds the **1%** threshold overall. Kalish 2024 notes IC2-LOM has lower overall risk (~**2–3%**), with many reported tumors being **HB**. Updated North American/Australian approach generally supports BWSp tumor surveillance, including **AFP + complete abdominal ultrasound every 3 months until age 3 years**, then **renal ultrasound every 3 months until age 7 years** (pqac-00000000, pqac-00000045) |
| **Paternal uniparental disomy of 11p15 / pUPD11 (upd(11)pat)** | Paternalization of both imprinting domains causes **IGF2 overexpression** with **silencing/reduction of H19 and CDKN1C**; often reflects mosaic LOH/pUPD affecting 11p15 and can extend into tumor tissue (pqac-00000034, pqac-00000041, pqac-00000042) | ~20% (pqac-00000005, pqac-00000042) | **Intermediate-high risk**: overall tumor risk **16%** (Kalish summary also **16–30%**); **Wilms tumor 7.9%**; **hepatoblastoma 3.5%**; neuroblastoma **1.4%**; adrenocortical carcinoma **1.1%**; pheochromocytoma **0.8%**; lymphoblastic leukemia **0.5%**; pancreatoblastoma **0.3%**; hemangiotheloma **0.3%** (pqac-00000005, pqac-00000000, pqac-00000042) | Strongly affected by mosaicism; blood epigenotype may differ from liver, kidney, or tumor. Organ-specific mosaicism is a major reason blood-based profiling can underestimate risk; SNP array/STR testing and multi-tissue sampling may be needed (pqac-00000016, pqac-00000046, pqac-00000019) | Clearly above **1%** threshold. Because both **WT** and **HB** risks are material, surveillance should include **complete abdominal ultrasound every 3 months until age 3 years** plus **AFP every 3 months until age 3 years**, followed by **renal ultrasound every 3 months until age 7 years**; adrenal glands should also be imaged given slightly increased adrenal tumor risk in BWSp, especially pUPD11 (pqac-00000045, pqac-00000000) |
| **Maternal CDKN1C pathogenic variant** | Loss-of-function of maternally expressed **CDKN1C** (cell-cycle inhibitor/tumor suppressor); paternal allele is normally silenced, so pathogenicity is dependent on maternal transmission/expression (pqac-00000034, pqac-00000042) | ~5% of sporadic cases; up to **40% of familial** cases (older reviews also cite ~5–10% overall) (pqac-00000005, pqac-00000042, pqac-00000006) | Overall malignancy risk is lower than IC1/pUPD groups; pooled data identified **neuroblastoma ~2.8%** in the CDKN1C subgroup, with no clear WT/HB excess in the datasets summarized by Kalish 2024 (pqac-00000001, pqac-00000000) | Not a methylation defect per se, but BWSp diagnostic workup must still consider mosaicism and blended etiologies; sequencing of **CDKN1C** is especially important in familial cases or when cleft palate/omphalocele/family history is present (pqac-00000015, pqac-00000013) | Kalish 2024 specifically notes **screen all BWSp patients except those with CDKN1C pathogenic variants** for WT/HB under their harmonized recommendation, reflecting the low WT/HB burden in this subgroup; counseling and phenotype-directed follow-up remain important (pqac-00000019, pqac-00000000) |
| **11p15 copy-number variants / chromosomal rearrangements** | Duplications/deletions/translocations involving IC1/IC2 and nearby imprinted genes can alter dosage/imprinting; many paternal duplications increase expression of paternally expressed growth genes, while phenotype depends on size, content, and parental origin (pqac-00000042, pqac-00000013) | ~2.5% for CNVs; chromosomal rearrangements are rare (<5% overall in some series) (pqac-00000005, pqac-00000042) | Quantitative subgroup-specific tumor percentages are less well established than for IC1/IC2/pUPD. Risk is generally considered within BWSp and may warrant caution when the lesion creates a paternalized 11p15 state (pqac-00000042, pqac-00000013) | CNVs may be missed if only methylation is assessed; recommended workup includes **MS-MLPA** for methylation + copy number, with **chromosomal microarray, karyotype, or FISH** to define breakpoints/rearrangements. Multi-tissue testing may still be needed if mosaic (pqac-00000013, pqac-00000016) | If the lesion confers BWSp with estimated tumor risk above **1%**, AACR-style surveillance principles apply. In practice, many clinically diagnosed BWSp patients undergo the same **US/AFP surveillance schedule** because precise blood-defined subgroup assignment may be unreliable in mosaic disease (pqac-00000052, pqac-00000019, pqac-00000046) |
| **No detectable molecular defect / clinically diagnosed BWSp** | No confirmed 11p15 lesion in tested sample despite clinical phenotype; may reflect low-level mosaicism, tissue-restricted epigenetic change, alternative diagnosis, or currently unsolved mechanism (pqac-00000014, pqac-00000019) | ~20% remain unsolved after standard testing (pqac-00000014, pqac-00000011) | Pooled cohort estimate from Maas: **~6.7%** tumor risk in patients without a detectable molecular defect (pqac-00000001) | Negative blood testing does **not** exclude BWSp. Additional tissues from affected sites can improve yield; blood/tumor discordance and organ-specific mosaicism are well documented (pqac-00000014, pqac-00000019, pqac-00000046) | Because estimated risk remains above **1%** and subgroup assignment may be falsely negative in blood, recent guidance favors **universal BWSp surveillance** in most patients: **complete abdominal ultrasound + AFP every 3 months to age 3 years**, then **renal ultrasound every 3 months to age 7 years** (except CDKN1C subgroup in the Kalish 2024 approach) (pqac-00000000, pqac-00000045, pqac-00000046) |


*Table: This table summarizes the major 11p15.5 molecular subtypes of Beckwith–Wiedemann spectrum, their core mechanisms, approximate frequencies, tumor risks, and surveillance implications. It is useful for linking subtype-specific biology to real-world testing and screening decisions.*