First-line next-generation sequencing could simplify 46,XY DSD diagnosis

medwireNews: Researchers recommend next-generation sequencing for the first-line diagnosis of patients with 46,XY differences of sex development (DSD).

In a cohort of 263 patients, 209 underwent sequencing (target gene or next generation) producing a molecular diagnosis in 59.3%, including for 21 patients with previously unclear aetiology.

Classification based on clinical and biochemical findings produced a diagnosis in 68.4% of patients, and combining the two methods resulted in 78.9% receiving a diagnosis.

Nathalia Gomes (Faculdade de Medicina da Universidade de São Paulo, Brazil) and co-researchers report that a molecular diagnosis was possible in 96.5% of patients with sex differentiation defects (95.9% of those with androgen synthesis disorders, 96.5% with androgen insensitivity syndrome and all of those with persistent Mullerian duct syndrome).

By contrast, molecular diagnosis was possible in just 36.0% of patients with gonadal dysgenesis and 31.8% of those with unknown aetiology.

“Therefore, massively parallel sequencing [ie, next-generation sequencing] should be incorporated as a first-line approach because it potentially decreases the complexity of the diagnostic workup by directing further testing to specific etiologies”, the team writes in The Journal of Clinical Endocrinology & Metabolism.

They add that “patients with hormone synthesis/action defects would be easily identified, substantially simplifying subsequent hormonal workup.”

Of note, one patient initially classified as having a defect of androgen secretion or action proved on sequencing to have a heterozygous pathogenic variant in MAP3K1, a gene involved in gonadal development. For all other patients, the genetic results matched the initial clinical/biochemical classification.

The study participants were a median age of 14 years at first evaluation, but the range encompassed 0.1 to 59 years. Based on phenotype alone, 27.7% were classified as having gonadal dysgenesis, 23.4% a disorder of androgen synthesis and 17.2% a disorder of androgen action, with the remaining 31.6% having an unknown aetiology.

“The high diagnostic rate of our clinical classification could be explained by the fact that most of our patients were first evaluated at puberty or adulthood”, say Gomes and team.

In all, 168 patients underwent sequencing of target DSD genes, which produced a definite or probable molecular diagnosis in 59.5%. Those who remained without a molecular diagnosis or where more information was required, plus 41 patients without previous genetic testing, underwent next-generation sequencing, producing a diagnosis in 30.4% of the 125 patients tested.

Of the patients with initially unclear aetiology, 11 of those in whom a molecular diagnosis was possible had androgen secretion/action defects and 10 had gonadal dysgenesis.

Despite advocating for first-line use of next-generation sequencing in patients with 46,XY DSD, the researchers stress that “clinical/biochemical evaluation was also absolutely required, as it supported the genetic findings especially in the presence of uncommon/novel variants and, in individuals without a molecular diagnosis, it was crucial to guide the treatment.”

They conclude: “Therefore, optimal strategy for diagnosing 46,XY DSD patients involves both clinical/biochemical and genetic approaches.”

Eleanor McDermid

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

J Clin Endocrinol Metab 2022; doi:10.1210/clinem/dgac064
Martin Savage
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