Case report of whole genome sequencing in the XY female: identification of a novel SRY mutation and revision of a misdiagnosis of androgen insensitivity syndrome.
BACKGROUND
The 46,XY female is characterised by a male karyotype and female phenotype arising due to any interruption in the sexual development pathways in utero. The cause is usually genetic and various genes are implicated.


METHODS
Herein we describe a 46,XY woman who was first diagnosed with androgen insensitivity syndrome (testicular feminisation) at 18 years; however, this was later questioned due to the presence of intact Müllerian structures. The clinical phenotype suggested several susceptibility genes including SRY, DHH, NR5A1, NR0B1, AR, AMH, and AMHR2. To study candidate genes simultaneously, we performed whole genome sequencing. This revealed a novel and likely pathogenic missense variant (p.Arg130Pro, c.389G>C) in SRY, one of the major genes implicated in complete gonadal dysgenesis, hence securing this condition over androgen insensitivity syndrome as the cause of the patient's disorder of sexual development.


CONCLUSIONS
This case highlights the emerging clinical utility of whole genome sequencing as a tool in differentiating disorders of sexual development.
Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia. Sunita.DeSousa@sa.gov.au.|Department of Genetics and Molecular Pathology, Centre for Cancer Biology, an SA Pathology and UniSA alliance, Adelaide, SA, Australia. Sunita.DeSousa@sa.gov.au.|School of Medicine, University of Adelaide, Adelaide, SA, Australia. Sunita.DeSousa@sa.gov.au.|Hormones and Cancer Group, Garvan Institute of Medical Research, Sydney, NSW, Australia. Sunita.DeSousa@sa.gov.au.
Sunita M C
SM
De Sousa
Department of Genetics and Molecular Pathology, Centre for Cancer Biology, an SA Pathology and UniSA alliance, Adelaide, SA, Australia.|School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
Karin S
KS
Kassahn
Department of Genetics and Molecular Pathology, Centre for Cancer Biology, an SA Pathology and UniSA alliance, Adelaide, SA, Australia.
Liam C
LC
McIntyre
Department of Genetics and Molecular Pathology, Centre for Cancer Biology, an SA Pathology and UniSA alliance, Adelaide, SA, Australia.
Chan-Eng
CE
Chong
Department of Genetics and Molecular Pathology, Centre for Cancer Biology, an SA Pathology and UniSA alliance, Adelaide, SA, Australia.|School of Medicine, University of Adelaide, Adelaide, SA, Australia.|School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.|ACRF Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia.|School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
Hamish S
HS
Scott
Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.|School of Medicine, University of Adelaide, Adelaide, SA, Australia.
David J
DJ
Torpy
D013734:Androgen-Insensitivity Syndrome / Q000175:diagnosis* / Q000235:genetics; D004252:DNA Mutational Analysis; D003951:Diagnostic Errors; D005260:Female; D015894:Genome, Human; D006061:Gonadal Dysgenesis, 46,XY / Q000175:diagnosis* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D051876:Sex-Determining Region Y Protein / Q000235:genetics*
C497745:SRY protein, human; D051876:Sex-Determining Region Y Protein
Androgen insensitivity syndrome; Case report; Disorders of sexual development; Gonadal dysgenesis; Next generation sequencing; SRY; Whole genome sequencing