Rare genetic discovery explains sex development differences in XY females

Two young girls in Vietnam are living proof that there is a lot more to sex than genetics, after being found to have an extremely rare sexual development condition.

Thanks to their doctors in Hanoi and researchers at Hudson Institute of Medical Research, they have been identified as XY females, and the exact source of their genetic difference has been identified for the first time.

Their findings are detailed in the Journal of Clinical Endocrinology & Metabolism, the leading journal for the study of differences of sexual development (DSD).

An incredibly detailed analysis of the siblings’ genetic makeup showed that a particular combination of variations from each parent gave them external female appearance and low testosterone levels despite having XY chromosomes.

Detailed genetic testing confirms difference of sexual development

The analysis was conducted by PhD student Shirin Moradi Fard under the supervision of DSD specialist Professor Vincent Harley.

Working with clinician-researcher, Dr Uyen Le, they studied the children’s genomes to a level of detail that has rarely been attempted previously, resulting in just the fourth confirmed case of this specific DSD worldwide.

“We describe the condition as compound heterozygote, the first example in this condition.” said Prof Harley. “That means a single genetic variation has been passed from each parent. These variations have no adverse effect individually, but when combined, they cause this DSD.”

Ms Moradi Fard says a mind-boggling level of genetic detail was examined to reach a confirmed diagnosis.

“Initial genetic tests looking at the coding regions of the patient DNA were inconclusive, so their doctors asked Dr Le and the team to consider genome sequencing,” she said.

“That means going from analysing around 3 million bases to analysing 3 billion bases.”

Looking beyond genetic coding

“We looked beyond the parts of DNA that code for proteins and found a change hidden deep within the CYB5A gene. I then tested this change in the lab and showed that it caused an extra piece to be added to the gene’s RNA message. This introduces an early stop signal, which is predicted to prevent the production of a working protein involved in making sex hormones.”

The family brought the children to see specialists in Hanoi over concerns the older child was not experiencing puberty, and initial genetic test failed to find a cause.

Prof Harley compares this study to searching for a needle in a haystack.

PhD student Moradi Fard’s in-house pipeline analysis was later replicated using a Swiss Artificial Intelligence (AI) system trained to identify genes associated with DSD, which confirmed its accuracy.

Dr Le then conveyed the findings to the clinicians in Vietnam.

“I told them we have very strong evidence to prove that this genetic variant is affecting the structure of proteins that are essential to sex development.”

The team believes the specifics of this DSD can be added to genetic screening during pregnancy for families in which it has previously been identified.

“This genetic condition is very specific to this family,” Dr Le said. “So, if they plan future pregnancies, especially through IVF, there can be a pre-natal diagnosis.”