PT  - JOURNAL ARTICLE
AU  - Stoltze, Ulrik Kristoffer
AU  - Hildonen, Mathis
AU  - Hansen, Thomas Van Overeem
AU  - Foss-Skiftesvik, Jon
AU  - Byrjalsen, Anna
AU  - Lundsgaard, Malene
AU  - Pignata, Laura
AU  - Grønskov, Karen
AU  - Tumer, Zeynep
AU  - Schmiegelow, Kjeld
AU  - Brok, Jesper Sune
AU  - Wadt, Karin A W
TI  - Germline (epi)genetics reveals high predisposition in females: a 5-year, nationwide, prospective Wilms tumour cohort
AID  - 10.1136/jmg-2022-108982
DP  - 2023 Sep 01
TA  - Journal of Medical Genetics
PG  - 842--849
VI  - 60
IP  - 9
4099  - http://jmg.bmj.com/content/60/9/842.short
4100  - http://jmg.bmj.com/content/60/9/842.full
SO  - J Med Genet2023 Sep 01; 60
AB  - Background Studies suggest that Wilms tumours (WT) are caused by underlying genetic (5%–10%) and epigenetic (2%–29%) mechanisms, yet studies covering both aspects are sparse.Methods We performed prospective whole-genome sequencing of germline DNA in Danish children diagnosed with WT from 2016 to 2021, and linked genotypes to deep phenotypes.Results Of 24 patients (58% female), 3 (13%, all female) harboured pathogenic germline variants in WT risk genes (FBXW7, WT1 and REST). Only one patient had a family history of WT (3 cases), segregating with the REST variant. Epigenetic testing revealed one (4%) additional patient (female) with uniparental disomy of chromosome 11 and Beckwith-Wiedemann syndrome (BWS). We observed a tendency of higher methylation of the BWS-related imprinting centre 1 in patients with WT than in healthy controls. Three patients (13%, all female) with bilateral tumours and/or features of BWS had higher birth weights (4780 g vs 3575 g; p=0.002). We observed more patients with macrosomia (>4250 g, n=5, all female) than expected (OR 9.98 (95% CI 2.56 to 34.66)). Genes involved in early kidney development were enriched in our constrained gene analysis, including both known (WT1, FBXW7) and candidate (CTNND1, FRMD4A) WT predisposition genes. WT predisposing variants, BWS and/or macrosomia (n=8, all female) were more common in female patients than male patients (p=0.01).Conclusion We find that most females (57%) and 33% of all patients with WT had either a genetic or another indicator of WT predisposition. This emphasises the need for scrutiny when diagnosing patients with WT, as early detection of underlying predisposition may impact treatment, follow-up and genetic counselling.Data are available on reasonable request. The corresponding author, who is the gaurantor of this work, can assist in exploring and facilitating avenues to data access. Full access to person-identifiable data requires relevant approvals in accordance with Danish data and ethical laws. Requests will be responded to within 30 working days. Metadata without identifiable data may be shared on reasonable request. The authors uphold the right to be informed of and assess any publication resulting directly from the original data provided in this publication.