In:
Journal of Medical Genetics, BMJ, Vol. 60, No. 9 ( 2023-09), p. 842-849
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0022-2593
,
1468-6244
DOI:
10.1136/jmg-2022-108982
Language:
English
Publisher:
BMJ
Publication Date:
2023
detail.hit.zdb_id:
2009590-9
SSG:
12
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