Table 2.

Less Common Genes and Syndromes Associated with Wilms Tumor Predisposition

GeneSyndromeMOIEstimated Wilms Tumor Risk 1Other Clinical Features
AMER1 (WTX) Osteopathia striata with cranial sclerosis XL~5%Sclerosis of cranium & long bones, macrocephaly, characteristic facial features, ±DD/ID
ASXL1 Bohring-Opitz syndrome AD~7%Growth deficiency, characteristic facial features, distinct posture, seizures. cardiac anomalies, DD/ID
BLM Bloom syndrome AR∼6%Growth deficiency, immune deficiency, sun sensitivity, diabetes, multiple cancers
BRCA2 BRCA2-related Fanconi anemiaAR∼20%-60%Growth deficiency, congenital anomalies, dysmorphic features, early-onset leukemia, medulloblastoma. pigmentary abnormalities
BUB1B Mosaic variegated aneuploidy syndrome (OMIM 257300)AR>85%Growth deficiency, microcephaly, CNS anomalies, dysmorphic features, genitourinary anomalies, DD/ID, nephroblastoma, rhabdomyosarcoma, leukemia.
CDC73 CDC73-related disorders AD∼3%Hyperparathyroidism, parathyroid adenoma & cancer, osseous fibroma(s) of the jaw
CHEK2 CHEK2 cancer susceptibility (OMIM 609265)AD∼3%Breast cancer, ↑ risk of some additional cancers (prostate, GI, sarcomas, renal)
CTR9 Familial WT 2AD>60%Paternally inherited
DICER1 DICER1 tumor predisposition AD<1% 3Pleuropulmonary blastoma, pulmonary cysts, thyroid gland neoplasia, ovarian tumors, & cystic nephroma, ciliary body medulloepithelioma, nasal chondromesenchymal hamartoma, pineoblastoma, pituitary blastoma
GLOW syndrome (See DICER1 Tumor Predisposition.)Somatic mosaic / AD 4Unknown; possibly >50%GLOW; also macrocephaly, characteristic facial features, autism
DIS3L2 Perlman syndrome (OMIM 267000)AR65%Fetal ascites, neonatal demise, macrosomia, characteristic facial features, visceromegaly, DD/ID
FBXW7 FBXW7-related Wilms tumor 5ADUnknownAdult-onset osteosarcoma (in 1 person); extrarenal rhabdoid (1 person); HL, FSGS, ovarian cystadenoma, & breast cancer (1 person) 6
GPC3
GPC4 		Simpson-Golabi-Behmel syndrome type 1 XL4%-9%Macrosomia, macroglossia. DD/ID, multiple congenital anomalies, hepatoblastoma, neuroblastoma, gonadoblastoma, hepatocellular carcinoma, medulloblastoma.
KDM3B KDM3B-related Wilms tumor 5AD<1%In 1 person each: hepatoblastoma, AML, HL
MLH1
MSH2
MSH6
PMS2 7		Constitutional mismatch repair deficiency (CMMRD) (See Lynch Syndrome.)AR<1%Multiple tumor types; predominantly brain tumors & GI tumors
NYNRIN NYNRIN-related Wilms tumor 5ARUnknownUnknown
NSD1 Sotos syndrome AD<3%Overgrowth, macrocephaly, DD/ID, leukemia, lymphoma, neuroblastoma, teratoma, & other cancer types.
PALB2 PALB2-related Fanconi anemiaAR∼40%Growth deficiency, multiple congenital anomalies, pigmentary abnormalities, medulloblastoma.
PIK3CA PIK3CA-related overgrowth spectrum Usually somatic mosaic1%-2%Disproportional overgrowth, brain malformations, DD/ID, lipomas, fibroadipose hyperplasia, vascular malformations
TP53 Li-Fraumeni syndrome AD<1%Multiple cancers: breast, adrenal cortical carcinoma, osteosarcoma, medulloblastoma, choroid plexus carcinoma, rhabdomyosarcoma, hypodiploid ALL.
TRIM37 Mulibrey nanism syndrome (OMIM 253250)AR6%IUGR, characteristic facial features, heart disease, skeletal anomalies
TRIP13 Mosaic variegated aneuploidy syndrome (OMIM 617598)AR~10%Growth deficiency, microcephaly, dysmorphic features, DD/ID

AD = autosomal dominant; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; AR = autosomal recessive; DD = developmental delay; FSGS = Focal segmental glomerular sclerosis; GI = gastrointestinal; GLOW = global developmental delay, lung cysts, overgrowth, Wilms tumor; HL = Hodgkin’s lymphoma; ID = intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance; WT = Wilms tumor; XL = X-linked

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One large family with multiple individuals with DICER1 tumor predisposition syndrome due to c.2407G>A (p.Gly803Arg) had four individuals with Wilms tumor [Palculict et al 2016].

4.

Somatic mosaic pathogenic variants affecting the RNase IIIb domain have been identified in several individuals with GLOW syndrome [Klein & Martinez-Agosto 2020]. Four individuals have been reported with a germline DICER1 pathogenic variant and additional clinical features overlapping with GLOW syndrome (e.g., skeletal findings, facial dysmorphism, developmental delay); one of the reported individuals also had a germline ARID1B pathogenic variant [Venger et al 2021].

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Wilms tumor has been reported in individuals with MLH1- and MSH6-related CMMRD [Citak et al 2021, Durno et al 2021]; It is unknown if biallelic MSH2 or PMS2 pathogenic variants increase the risk of Wilms tumor.

From: Wilms Tumor Predisposition

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