Michele Rapp, a genetic counselor at Children’s Hospital Colorado’s DSD clinic, sees patients across the pediatric spectrum. When explaining a genetic DSD diagnosis, she starts with the building blocks: Legos.

 

“Oftentimes, when kids get Legos kits they come with instructions of how to build the structure the way it was intended to be built, and so that’s a lot like our genes. They’re the guidebook for how we put our own pieces, or Legos, together that makes us who we are and how we are built,” Rapp said.

 

“Sometimes there can be alterations and differences in what those structures look like from person to person and that results in our unique differences,” she said, explaining how she describes a genetic difference to a young patient. 

 

Emphasizing the beauty of difference rather than the shame associated with it is helpful for patients’ morale, Rapp said. 

 

“We’re not doing really in-depth things but having them just know from the get go that we want them to have that self-confidence and self-esteem,” Rapp said.

 

Many genes can influence sex development. They could be genes we typically think of as being involved in the process, like SRY or SOX9, but they could also be genes we never realized played a role.

 

While findings of new genes and their mechanisms are exciting discoveries for scientists at the bench, why does it matter for clinicians and patients? 

 

Allison Weisman is a genetic counselor at Lurie Children’s Hospital in Chicago, where she works in the Supportive Program for a Range of Urogenital Traits, or SPROUT, clinic. Weisman meets with patients and their families and collaborates with doctors to help identify their specific DSD diagnosis and its genetic underpinnings, as this information can help understand what medical interventions the patient may need. For example, it can help explain to patients what they can expect at puberty, future fertility outcomes, hormone needs and potential risks for associated diagnoses like gonadal tumors, congenital heart defects or thyroid disease. 

 

Weisman describes her role as that of a translator.

 

“We are there to help answer the question of ‘why’ and ‘what does that mean?’” Weisman said. 

 

Genetic counselors can help discover a diagnosis at different time points, including prenatal consultation, at birth or during puberty. Prenatal genetic testing analyzes free-floating fetal DNA in the mother’s bloodstream. Sometimes genetic counselors may see that the fetus’ chromosomal makeup does not match with ultrasound images suggesting their anatomical sex.

 

At birth, if there is already suspicion for DSD due to ultrasound incongruencies or ambiguous genitalia at birth, clinicians may order two types of tests, karyotyping and in-situ hybridization. Karyotyping allows genetic counselors to visualize all of the patient’s chromosomes and search for structural differences, like a missing or translocated SRY gene. In-situ hybridization involves collecting a small sample of a patient’s cells, staining them with a fluorescent probe and visualizing their X and Y chromosomes to see how many there are. 

 

If those initial tests are inconclusive, genetic counselors may proceed with more extensive options, like whole genome sequencing. Sequencing is the process by which DNA is read and allows genetic counselors to read the patient’s genetic code. 

 

“Whole genome sequencing is literally spelling out every single DNA letter of our 20,000 genes,” Rapp said. 

 

Genetic testing is powerful, and it can reveal more information than just what is relevant for the DSD diagnosis. It can reveal incidental findings, which are genetic risks unrelated to the goal of the tests, such as risk for future diseases. Weisman said it is important to strike a balance with transparency and also respecting family wishes when sharing test results. 

 

“I don't think we're gatekeepers,” Weisman said. “A big part of it is that pre-test counseling, helping families understand the potential types of results, and making decisions about how much information they want to know.” 

 

Pre-test counseling also involves explaining to families that genetic testing does not guarantee a definitive diagnosis. Sometimes they may find a significant genetic variant involved and sometimes they may find a variant that they don’t know the impact of. 

 

After counseling and discussing family histories, the medical team collects a biological sample from the patient, usually blood (about two teaspoons) and sends it to an outsourced lab. Blood is preferred to saliva because it typically contains more DNA. The lab isolates DNA from the blood and sequences it. 

 

Here is where a genetic counselor’s investigation begins. They look through the test results and analyze any specific variants in genes and whether they resulted in a protein change. Then, they search for published research articles to learn more about the gene, such as studies using stem cells or animal models, and potential case studies of other individuals with the same change. 

 

“I really see, again, my job as that translator or that interpreter, as someone who's not just interpreting that genetic test information and then applying it to the patient, but interpreting it in the context of what is known, what is out there, and so I'm synthesizing that data,” Weisman said. 

 

When presenting results to patients and families, genetic counselors have to consider a wide range of factors, such as how to communicate potentially pathogenic findings in a sensitive manner. 

 

“When doing an initial disclosure, I do cover everything very broadly,” Weisman said. “I also, you know, try to find them reputable research that they can read that's appropriate for their health literacy.”

 

Age-appropriateness is also important, and genetic counselors often work alongside clinical psychologists to help parents explain the diagnosis and its influence on genital appearance, puberty or fertility to their children depending on their age.

 

“You wouldn’t tell a four year old those things. They can't comprehend that. But maybe you help a four year old understand that everybody is different,” Weisman said.

 

Weisman said that for children around ages eight to 11, the clinical team provides anticipatory guidance about what puberty could look like. When patients start to get older, they discuss heavier topics like cancer and fertility. Psychologists and genetic counselors work together on these readiness assessments to determine when and how is the best time to explain different aspects of the diagnosis. 

 

Rapp said she encourages parents to share information with their children to mitigate stigma. For example, she shared an example of a nine-year-old patient at the Children’s Hospital Colorado clinic.

 

“‘I already know I don't have any testes and I don't have any ovaries. I'll have kids my own way because I want to be a dad,’” Rapp recalled the patient saying. “He knew what was going on with him in his body because his parents had already talked to him.”

 

Currently, only about 30-50% of DSD patients can determine their diagnosis via even the most comprehensive genetic tests. Sometimes patients have to wait years before getting a definitive diagnosis, and families often face test fatigue.

 

“Genetics is in its infancy compared to other medical fields,” Weisman said. Scientists have not yet uncovered the purpose and functions of all 20,000 human genes, let alone the 98% of the genome that does not directly code for protein-building instructions but instead by serve regulatory purposes.

 

“The more we learn, the more questions there are,” Weisman said. 

 

As we learn more about what genes are involved in sex development, genetic counselors will continue to serve as a key conduit between patients, families, physicians and science to optimize care.