IMPE2023 Poster Presentations Sex Differentiation, Gonads and Gynaecology, and Sex Endocrinology (19 abstracts)
WT1 deletion in 46,XY DSD – the importance of copy number variant analysis
Gabby Atlas 1,2,3 , Katrina Bell 2 , Gorjana Robevska 2 , Jocelyn Van Den Bergen 2 , Peter Ivan Hadiprajitno 4 , Nurin Listyasari 5 , Ardy Santosa 6 , Sultana M.H. Faradz 5 , Katie Ayers 2,3 & Andrew Sinclair 2,3
1Royal Children's Hospital, Melbourne, Australia. 2Murdoch Children's Research Institute, Melbourne, Australia. 3University of Melbourne, Melbourne, Australia. 4Faculty of Medicine, Diponegoro University, Semarang, Indonesia. 5Diponegoro University Hospital, Semarang, Indonesia. 6Department of Urology, Dr. Kariadi Hospital, Semarang, Indonesia
A 2 year old boy presented with penoscrotal hypospadias, bilateral undescended testes and a bifid scrotum. Initial biochemical workup was not suggestive of a particular underlying diagnosis and he underwent orchidopexy and hypospadias repair. In collaboration with an international team, research genetics was undertaken to look for a cause for his undiagnosed 46,XY DSD. Whole exome sequencing was performed as a trio analysis (with a virtual DSD gene panel comprising 109 genes) and no pathogenic or likely pathogenic variants were found. Using Ximmer (1), a locally developed tool for copy number variant (CNV) detection, whole exome sequencing data was analysed to reveal a rare WT1 deletion. Microarray confirmed an interstitial deletion of approximately 0.17 megabases from chromosome region 11p13, including the autosomal dominant gene WT1. Deletions of WT1 are known to be associated with 46,XY gonadal dysgenesis as well as Wilms tumour and gonadoblastoma, prompting further surveillance by the patient’s local team. Overall, CNVs are estimated to comprise >20% of DSD (2-4). This case highlights the importance of undertaking CNV analysis in the genetic work-up for DSD, and supports the use of CNV-calling tools when analysing genomic data. 1. Sadedin SP, Ellis JA, Masters SL, Oshlack A. Ximmer: a system for improving accuracy and consistency of CNV calling from exome data. Gigascience. 2018;7(10). 2. Ledig, S., et al., Array-CGH analysis in patients with syndromic and non-syndromic XY gonadal dysgenesis: evaluation of array CGH as diagnostic tool and search for new candidate loci. Hum Reprod, 2010. 25(10): p. 2637-46. 3. Tannour-Louet, M., et al., Identification of de novo copy number variants associated with human disorders of sexual development. PLoS One, 2010. 5(10): p. e15392. 4. Croft, B., T. Ohnesorg, and A.H. Sinclair, The Role of Copy Number Variants in Disorders of Sex Development. Sex Dev, 2018. 12(1-3): p. 19-29.
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