Next-Generation Sequencing Reveals Novel Genetic Variants (SRY, DMRT1, NR5A1, DHH, DHX37) in Adults With 46,XY DSD.

Federica Buonocore,Jenifer P Suntharalingham,Gerard S Conway,Carlos F Lagos,John C Achermann,Elim Man,Gill Rumsby,Tom F J King,Niccolò Striglioni,Lin Lin,Oliver Clifford-Mobley,Ignacio Del Valle

doi:10.1210/js.2019-00306

Federica Buonocore, Jenifer P Suntharalingham + Show 10 more

Open Access

https://doi.org/10.1210/js.2019-00306

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Abstract

ContextThe genetic basis of human sex development is slowly being elucidated, and >40 different genetic causes of differences (or disorders) of sex development (DSDs) have now been reported. However, reaching a specific diagnosis using traditional approaches can be difficult, especially in adults where limited biochemical data may be available.ObjectiveWe used a targeted next-generation sequencing approach to analyze known and candidate genes for DSDs in individuals with no specific molecular diagnosis.Participants and DesignWe studied 52 adult 46,XY women attending a single-center adult service, who were part of a larger cohort of 400 individuals. Classic conditions such as17β-hydroxysteroid dehydrogenase deficiency type 3, 5α-reductase deficiency type 2, and androgen insensitivity syndrome were excluded. The study cohort had broad working diagnoses of complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25), a group that included partial gonadal dysgenesis and those with a broad “partial androgen insensitivity syndrome” label. Targeted sequencing of 180 genes was undertaken.ResultsOverall, a likely genetic cause was found in 16 of 52 (30.8%) individuals (22.2% CGD, 40.0% pvDSD). Pathogenic variants were found in sex-determining region Y (SRY; n = 3), doublesex and mab-3–related transcription factor 1 (DMRT1; n = 1), NR5A1/steroidogenic factor-1 (SF-1) (n = 1), and desert hedgehog (DHH; n = 1) in the CGD group, and in NR5A1 (n = 5), DHH (n = 1), and DEAH-box helicase 37 (DHX37; n = 4) in the pvDSD group.ConclusionsReaching a specific diagnosis can have clinical implications and provides insight into the role of these proteins in sex development. Next-generation sequencing approaches are invaluable, especially in adult populations or where diagnostic biochemistry is not possible.

Highlights

It is more than 25 years since SRY was identified as the main testis-determining gene in humans and mice and as a cause of 46,XY differences of sex development (DSD)[1,2,3]
Whilst the diagnosis of specific forms of sex chromosome DSD (SCDSD) and 46,XX DSD can usually be made with karyotyping or biochemical analysis, the specific diagnosis of 46,XY DSD is often more challenging
46,XY DSD is commonly divided into conditions affecting gonad development or conditions affecting androgen biosynthesis and action

Summary

Introduction

It is more than 25 years since SRY was identified as the main testis-determining gene in humans and mice and as a cause of 46,XY differences (disorders) of sex development (DSD)[1,2,3]. At least 40 other genetic causes of DSD have been reported, but the relative contribution to these genes within the clinical setting is poorly documented[4,5,6]. 46,XY DSD is commonly divided into conditions affecting gonad (testis) development (e.g. complete gonadal dysgenesis, known as Swyer syndrome) or conditions affecting androgen biosynthesis and action. E and usually affect the adrenal gland as well as the gonad More specific defects in testosterone biosynthesis (17β-hydroxysteroid dehydrogenase deficiency type 3, HSD17B3),

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