Speed Poster ESA-SRB-APEG-NZSE 2022

Outcomes of genomic testing for 46, XY Differences of Sex Development (#76)

Michele A O'Connell 1 2 3 , Gabby Atlas 1 2 3 , Hazel Phillimore 4 , Tiong Tan 2 3 4
  1. The Royal Children's Hospital, Melbourne, Melbourne, VIC, Australia
  2. University of Melbourne, Melbourne
  3. Murdoch Children's Research Institute, Melbourne, Victoria, Australia
  4. Victorian Clinical Genetics Services, Melbourne, Victoria, Australia

Genomic sequencing of DSD-related genes commenced at Victorian Clinical Genetics Service (VCGS) in March 2018.  The DSD panel comprises >70 genes with validated gene-disease association listed on PanelApp Australia (https://panelapp.agha.umccr.org/panels/99/). Our objective was to review the outcomes of DSD-related genetic testing performed at VCGS between March 2018 and Dec 2021. 

A retrospective review was conducted.  Clinical and demographic information provided at referral for genomic testing were extracted.  Outcomes of interest included the range of pathogenic (Class 5), likely pathogenic (Class 4) variants and variants of unknown significance ([VUS] Class 3a)1 reported, the overall diagnostic yield in the cohort and associations with clinical features.

Data from 155 individuals with 46,XY DSD were included. Pathogenic (n=28) or likely pathogenic (n= 8) variants consistent with DSD phenotype were found in 36/155 (23%) individuals, across sixteen different genes. AR(n=8; all assigned female), NR5A1(n=6) and  SRD5A2(n=5) variants were most common. Diagnostic variants were identified in n=15/36(41%) and n=22/118(19%) assigned females and males respectively. Additional extra-genital clinical features were reported in 7/36(19%). DSD-relevant Class 3a VUS were also reported in 6/155(4%), with segregation testing recommended.  A further six individuals had one copy of a DSD-relevant pathogenic / likely pathogenic variant but no ‘second-hit’ to explain the diagnosis. 

Genomic testing has confirmed a DSD-diagnosis in ~1/4 of individuals tested over the initial 4 years at VCGS.  Higher diagnostic rates were found in those with (predominantly-) female genital phenotype; however, a majority of this subset remains undiagnosed.  No individual with 46,XY DSD and male-appearing genitalia had an AR variant, highlighting the relative infrequency of a diagnosis of partial androgen insensitivity syndrome in 46XY DSD in the era of genomic testing.   These findings assist with optimising clinical decisions (e.g. gonadal management - AR, dihydrotestosterone replacement -SRD5A2) and along with longitudinal clinical follow-up will improve our understanding of DSD.

  1. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.