Meet our brilliant minds: Professor Andrew Sinclair

Sex Development

It’s the all-important question that every parent wants to know about their newborn– is it a boy or a girl? But what happens when no clear answer can be given?

Disorders of sex development (DSDs), which can be as frequent as one in 250 or as rare as one in 4500 births, can result in ambiguous genitalia, infertility and are associated with paediatric cancers of the testes and ovaries. “Uncertainty about a child’s sex is extremely traumatic for the individual, parents and other family members and carries profound psychological and reproductive consequences for the patient,” says Deputy Director Andrew Sinclair, who is internationally renowned for his work researching DSDs.

The cause of these problems is often a breakdown of the complex network of genes responsible for proper development of testes or ovaries in the embryo. In 1990, Andrew began unravelling the mystery surrounding some of these disorders when he identified the gene responsible for testis development, called SRY – for sex region on the Y chromosome. The finding was published in the journal Nature and lauded by the editor as one of the greatest genetic breakthroughs of the last century.

The importance of this discovery cannot be overstated. The SRY gene kick-starts the development of testis in the embryo. It provided an answer to one of the most fundamental questions – what makes us male or female? It has allowed Andrew’s team to substantially improve the diagnostic rates for DSD patients.

However, for about 60 per cent of cases, a diagnosis can still prove elusive. “For many of these children, no precise diagnosis can be given. That means there is no way to work out what the proper management should be,” Andrew says. For example, some forms of DSDs can result in individuals with XY chromosomes, who would normally present as male, being female. Likewise, individuals with XX chromosomes can be male.

Andrew’s team has substantially improved diagnostic rates for this group of DSD patients. “A lot of our work is about understanding how ovary and testis development occurs normally, and how we can, by understanding those genes, provide a better diagnosis to these children and their families.” “By using genomics – sequencing all of an individual’s genes – we have more than doubled DSD diagnoses,” says Andrew, who with Institute Director Kathryn North is leading the nation in a move to place genomics squarely within the Australian health care system.

At the same time as the SRY discovery, Andrew also identified a new family of related genes, called SOX, which play huge roles in normal human development. Over the years, his team has identified many more genes associated with DSD and developed a rapid diagnostic genomic technique for the disorders. It is hoped this technique will this year be translated into a clinical test through the Victorian Clinical Genetics Service to lift diagnostic rates further.

Andrew also leads a national group of researchers trying to find the underlying cause for the most common DSD affecting one in 250 boys, hypospadias, where the urethra develops abnormally. Girls who experience early ovarian failure could also benefit from his research. Premature ovary insufficiency, which can occur in teenagers and causes infertility, is a devastating revelation for adolescents. “Essentially, when there is the collapse of the ovary function, it just stops working,” says Andrew. “Obviously these girls are going to be infertile, but there are also hormonal effects that can be quite distressing. Early diagnosis means girls are offered the option to freeze their eggs, should they wish to use IVF to conceive later in life.”

By studying a large cohort of these women, Andrew’s team has identified new genes associated with early ovarian failure. Importantly, these genes are also implicated in a range of other developmental conditions and cancers, providing an even greater impetus to inform affected individuals as early as possible of the impacts on their overall health. The father of two teenagers, Andrew balances his roles at the Institute with the Executive Director position at the Victorian Clinical Genetics Services.

He enjoys films, theatre, surfing and bushwalking - when time allows. He’s an environmentalist at heart, a passion he traces back to an early love of biology. It’s perhaps this keen sense of social justice that drives him to provide answers for DSD patients.

With one in 4,500 babies born with ambiguous genitalia, Andrew’s lab receives DNA samples from individuals around Australia and the world seeking diagnostic answers. “It is a very fraught area,” says Andrew. “It influences so much about how you see yourself in society and how people treat you. It can be very difficult for people to navigate their way through life without a clear answer – we aim to find a diagnosis to give them clarity.” 

More information

View Professor Andrew Sinclair's researcher profile

Learn more about reproductive development research at Murdoch Children's