Rare genetic syndrome identified in children

A research team led by the Murdoch Children’s Research Institute (MCRI) has identified a new rare genetic syndrome that causes intellectual disability and differences of sex development (DSD) in children — a discovery that paves the way for diagnoses in more affected individuals and could lead to the development of new treatments.

The team’s study, published in the journal Nature Communications, describes nine children from six families in Europe, Israel and North Africa who have intellectual disability, delays in reaching developmental milestones and neurodevelopmental changes. The children with male sex chromosomes (XY) also had a difference of sex development (atypical development or appearance of the gonads and external genitals). In these children, disruption to testis development (termed gonadal dysgenesis) meant reduced production of the masculinising hormone, testosterone, and female or atypical male genital appearance.

The team found that all affected children in these six families carry recessive variants in a gene called SART3, inherited from both parents, in the first known report of variants in the SART3 gene causing a congenital syndrome. The researchers have suggested this new SART3-related condition be coined INDYGON (Intellectual Disability, Neurodevelopmental Defects and Developmental delay with 46,XY GONadal dysgenesis).

“The diagnosis of causative variants in the SART3 gene and INDYGON syndrome means the affected individual can be provided with the optimal clinical care and can access early support for their intellectual disability and developmental delay,” said study co-leader Dr Katie Ayers. “Having a correct genetic diagnosis means that carrier testing is also possible for families.”

According to Ayers, having a correct genetic diagnosis would help the young person and their family to understand differences in their gonadal and genital development and inform decisions about potential therapeutic interventions. She also noted that, although it appeared that the children with SART3 variants and XX chromosomes had functional ovaries, some of these children are still young.

“Monitoring their developing ovaries is particularly crucial during and after puberty as, if it is found that they are not functioning properly, hormone replacement may be necessary for their health and wellbeing,” she said. “Similarly, children with XY chromosomes who did not develop fully functional testis may be at risk of developing gonadal cancer, which also requires monitoring.”

After finding the SART3 genetic changes, the team studied the molecular function of SART3 using fruit fly models and showed that the gene has a crucial role in testicular and brain development. They then introduced SART3 gene variants into human pluripotent stem cells and found that these cells had abnormal development in brain or gonadal models, which confirmed that the changes found in the affected children were the likely cause of disruptions to gonadal and neuronal development.

The researchers now aim to better understand this new syndrome, and hope in future to provide insight into how this condition arises and highlight new paths to treatments for these children.

Image credit: iStock.com/LeticiaWoest