by Amber Freed

When you have a child, you want the best for that child in every way. This includes access to whatever healthcare is required for a healthy life. For parents of children born with a genetic disorder, a correct diagnosis is the first step to receiving that care. Because children with a rare disease have a small window in which treatment will be effective, a speedy diagnosis is essential. Unfortunately, a number of factors that are largely logistical and financial typically consume time and money just to get the rare disease diagnosis. Just what are the factors that make the Diagnosis Odyssey so challenging?

Lack of resources

Unless you have a physician in the family or live near a center of excellence and somehow get an appointment immediately for your concerns, most parents have a period during which they are the only ones who are sure there is a problem. With a rare genetic disease, it is possible that their pediatrician has no experience with the disorder. It is even possible with ultra-rare diseases affecting a handful of children worldwide, that there have been no studies published on the disorder. Waiting until the time your child’s doctor decides that there is no doubt there is a problem can be frightening and frustrating. It’s also very stressful because time that cannot be regained is flying by. 

Doing it Yourself

For many parents, the answer is to figure it out for themselves. These efforts range from searching online to visiting specialists who might be able to help – often specialists at a distance from home or outside their medical plan. When all else fails, many parents set out to educate themselves in the area that seems the most likely to be associated with the developmental delays they are observing. When the disease is ultra-rare, there is often no information to be found in their searches. For most parents, going to a site for rare diseases such as NORD (National Organization for Rare Disorders) is not an obvious choice. Many don’t arrive at this site until after diagnosis because they are searching on symptoms or developmental delays rather than a specific disorder.

Searching for Answers

Brittany Stineman’s son Nash has a disorder called SMARD (spinal muscular atrophy with respiratory distress). This disease causes infants to lose voluntary muscular functions such as breathing and swallowing. Because the symptoms are alarming, Brittany began her search soon after Nash was born. “Nash was born, and he was thriving,” Brittany says. “And then, all of a sudden it was like this immediate stop. He stopped thriving. And there was a problem with his breathing then, too. So, I was Googling intrauterine growth restriction [his diagnosis before he was born], failure to thrive, laryngomalacia, and everything else that occurred from the moment he was born. And it just kept coming.” Brittany’s searching led to the proper diagnosis early on, but she ruled it out because Nash didn’t fully fit the description. “He was still doing things and was way too strong at the time,” she explains before adding, “So initially, only a mother’s instinct would be able to really pinpoint that there was a serious problem. But I didn’t think it was going to be this serious, to be quite honest, but I knew it was going to be something. I just didn’t know what.”

There was no realistic way for Nash to wait; he clearly needed some sort of intervention. “I started bringing him into the hospital when he was around four months,” Brittany says. “After three hospitalizations and a hospital transfer, seven months later, we finally got a diagnosis after six weeks of begging our local hospital to do genetic testing, which they refused. Once I was finally able to get a transfer to a top three institution, they rushed his genetic testing and had the results in five days.” 

Nash’s diagnosis included the information that his life expectancy was 13 months – and he was 11 months at the time. “My husband and I were like, ‘No. He’s not dying in two months. Nobody’s putting an expiration date on my kid. We’re going to figure this out. We’ve gotten this far.”

Brittany’s research led her to a clinical trial that was not the right one for her son. At first she didn’t understand why, so she finally went where the trial was being held and said, “‘I’m here to talk to somebody, and I’m not leaving here until somebody gives me an answer. Actually,’ she says she added, ‘you have 24 hours to call me back, and if I don’t hear from Brian Kaspar (who is like the godfather of gene therapy), I’m coming back with my sleeping bag.’ The receptionist called somebody over and she said, ‘This mom has a son with a really rare form of SMA that’s been told doesn’t qualify for this clinical trial. And she said if she doesn’t hear from Brian Kaspar in 24 hours, she’s coming back with a sleeping bag, and she’s not kidding.’”

That night, Brian Kaspar called her back. He spent a lot of time explaining why Nash didn’t qualify and ended by telling Brittany, “You can develop it for him.”

Genetic Testing

Most rare diseases are monogenic – caused by a mutation to a single gene. A family history, prenatal testing, or discussions with a genetic counselor before a pregnancy will neither identify nor prevent a monogenic mutation since it occurs at an unspecified time during the child’s development. Because of this, genetic testing of the child after birth is the key to effective therapy for every child with a genetic disorder. The benefits of genetic testing include the ability to return genetic test results for a genetic condition that identify the single gene involved – essential for those with a health condition that is caused by a mutation in a single gene. 

So why not test right away? The cost. Brittany explains, “The hospital is so resistant to even doing the testing because it’s so expensive. And if health insurance doesn’t pick it up, then the hospital’s responsible for it. And it turns into the money game. And so they don’t want to do the testing unless they feel strongly that they’re going to find something. But then they [use a targeting sequence and] put themselves in a worse position to find something because they don’t even [provide the detailed clinical information required to arrive at an accurate diagnosis].

“It’s just so frustrating,” Brittany says, “and it’s happened to a lot of families that I’ve worked with, and so just that in and of itself. And then you feel lost. We were lucky. We got the genetic diagnosis right away because Nash had one key characteristic feature of his diagnosis that was very indicative, which was diaphragm paralysis. And there’s really only one other disease that would present like this in infancy. Cincinnati did a wonderful job reporting his clinical symptoms to the genetics company.” 

One way to make genetic testing more efficient and cost-effective is to consider which of the available types of genetic sequencing will be best for that child’s diagnosis and what type of health information and medical history must be made available before the testing is performed.

Types of Genetic Tests

Genetic testing is expensive, but with genetic testing it’s possible to pinpoint the cause of a specific disease. The health care provider can work with family members to identify the best type of test, with the understanding that the more inclusive and sensitive the test, the more expensive it will be. Also, the more inclusive and sensitive the test, the less reliance there will be on clinical notes before the testing is performed:

1. Targeting sequencing, sequences short pieces of DNA in the area identified as most likely to be associated with the disorder. Accurate clinical notes and observations are vital when selecting the portion of the DNA to be sequenced, since the sequence chosen will be based on the suspected condition or disease state. The results from this type of sequencing will be known in a matter of days. However, since it tests only a small portion of the DNA, an accurate diagnosis depends upon testing the correct portion. When the characteristics are very indicative of the genomic disorder, as was the case with Nash, targeting sequencing can be an excellent choice. A cheek swab can often be used for this type of testing, as bacteria in the sample is not a negating factor.

2. Whole-exome sequencing is a next-generation sequencing (NGS) method focusing on the protein-coding region of the patient’s genes. Although this represents less than 2% of the genome, it contains about 85% of known disease-related variants. Whole-exome testing will return results that identify the results of genetic changes, i.e., mutations. Whole-exome sequencing uses a blood sample and is an efficient, cost-effective alternative to whole-genome sequencing. It is also not limited to a specific targeted sequence so there is not a high risk of a negative result or false diagnosis.

3. Whole-genome sequencing (WGS) does just what it says – sequences the entire genome. A blood sample is used, and WGS takes time, but it can detect variations that whole-exome sequencing would miss. WGS is the most comprehensive test and can cut the median time to diagnosis significantly. It is also the most expensive test, although WGS testing is currently being used in a number of applications with the cost of the testing declining as a result.

With any method, clinical notes and observations may be required to home in on the relevant mutation. However, whole-exome sequencing and whole-genome sequencing do not depend upon specific patient observation at the start because there is not a choice to make about the section of DNA to test. If every child received whole-exome or whole-genome testing at the start of the diagnostic odyssey, the savings in time and money spent on fruitless efforts would be significant for the family, healthcare team, and insurance company.

Next Steps

A diagnosis doesn’t mean a clear path forward. There isn’t a protocol at most hospitals that describes next steps for parents to take when they must develop a cure. We’ll explore those next steps in the next article in this series.

Resources for Genetic Testing

These companies offer genetic testing upon request from a parent and/or a physician. The prices vary and the information required to accompany the test for an accurate diagnosis varies, so be certain to ask exactly what will be helpful in arriving at your child’s diagnosis.

Invitae has free genetic testing for anyone exhibiting neurological symptoms through its Behind the Seizure program.

Illumina is committed to ending diagnostic odysseys for rare diseases through whole-genome and whole-exome sequencing.

Commercial Labs Doing Whole Exome Sequencing Clinically:

Below is a list of more labs doing whole-exome sequencing. Please note: it is important to talk with your provider.



Perkin Elmer

MNG (Labcorp)




There are many more hospital/academic institutions that may offer WGS as well.

American Gene Technologies (AGT) sponsored this article in support of Maxwell and Amber Freed, children with SLC6A1, and families affected by rare diseases. AGT is a biotechnology company in Rockville, Maryland developing genetic medicines for rare diseases, starting with its lead program for Phenylketonuria (PKU). The AGT team deeply supports the rare disease community and, like Amber Freed, we believe in providing families with the resources and information they need to find applicable solutions to rare diseases while treatments are still in development. AGT also supports raising national awareness for the need of increased support, funding, and research for rare diseases. Learn more about AGT here:

SLC6A1 Gene

I am a mother of a beautiful boy with an SLC6A1 mutation and I am dedicated to finding the best treatment possible for my son.