Exome sequencing refines 46,XY DSD diagnosis

By Eleanor McDermid, Senior medwireNews Reporter

Exome sequencing can identify a likely genetic cause of 46,XY disorders of sex development (DSD) in about a third of cases, report researchers.

The team performed exome sequencing of DNA from 40 children with 46,XY DSD and analysed the results against a list of 64 genes known to be involved in sex determination, sex differentiation or central causes of hypogonadism.

This produced genetic diagnoses in 14 (35%) patients, and identified an additional six (15%) patients with genetic variants “of uncertain clinical significance”, Eric Vilain (University of California, Los Angeles, USA) and colleagues report in TheJournal of Clinical Endocrinology & Metabolism.

Commenting on the study for medwireNews, Faisal Ahmed, Consultant in Paediatric Endocrinology at the Royal Hospital for Sick Children in Glasgow, UK, said that with exome sequencing “we have to be quite open about possible genes of what they call uncertain significance; they may have some role to play.”

The genetic diagnoses identified by the team included four patients with mutations in the MAP3K1 gene, which has only recently been associated with complete gonadal dysgenesis.

The relatively high frequency of cases in this study suggests the MAP3K1 variant could be more common than anticipated. However, Ahmed noted that just one child had a mutation in the androgen receptor gene, despite these reportedly occurring in about 30% of children with 46,XY DSD, implying that the selection procedure for the study created an atypical group of patients.

He added that different studies tend to find that different variants are more common. “It’s all to do with small numbers.”

Other genetic diagnoses were two mutations in the WT1 gene, which has also been linked to gonadal dysgenesis, one STAR gene variant, and a LHCGR variant that explained the patient’s Leydig cell hypoplasia but not their lack of response to exogenous testosterone. Two patients had mutations in the gene encoding the anti-Müllerian hormone receptor, and four had mutations in genes thought to underlie androgen insensitivity syndrome.

Ahmed explained that knowing the underlying genetic fault helps to predict how patients will respond to treatment. For example, a boy with a mutated androgen receptor will not respond to testosterone treatment. It also helps to guide further testing in instances where the protein encoded by a gene exerts multiple effects.

In the UK, exome sequencing is being used as a research tool, but is not yet a clinical service. Although it is no more expensive than sequencing specific genes, Ahmed noted that exome sequencing “is a much more complex area and we do need the right level of skills to interpret the data.”

He highlighted that the researchers’ findings came via weekly meetings of a large number of experts, including geneticists, genetic counsellors and clinicians. “That’s the expensive part, getting the resources to interpret the data,” said Ahmed.

Nevertheless, he believes that exome sequencing “is the way things will move in the future.”

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