The Forgotten Amendment: A Newborn’s Right to Whole Exome Sequencing

From KIF1A.ORG February 3, 2017August 5, 2019

By Luke Rosen

On December 18, 2014, President Obama signed into law an amendment to the Newborn Screening Saves Lives Reauthorization Act of 2014 giving the Secretary of Health and Human Services authority to regulate newborn screening tests. Before this amendment was passed, newborn screening polices varied from state to state. The amendment included new tracking measures to ensure babies with deadly yet treatable disorders are diagnosed quickly.

Since the bill passed, not a single federal action has been applied to state-controlled newborn screening policies. Failure to implement any regulations on this act is preventing me from finding a cure for our daughter’s rare disease.

The Obama administration forgot about the amendment, and the new Secretary of Health and Human Services, Tom Price, is no champion of rare-disease advocacy. President Trump almost certainly will not make the Newborn Screening Saves Lives Reauthorization Act of 2014 a priority. This federal negligence has rendered the amendment moot and is responsible for misdiagnosis, lack of treatment and unaffordable child healthcare.

An amendment requiring Whole Exome Sequencing for babies who do not reach developmental milestones in the first twelve months of life must be passed immediately. Whole Exome Sequencing will save thousands of children from rare disease and early death.

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The marriage of precision medicine and broad genetic investigation recently gave birth to Whole Exome Sequencing (WES), a single test able to identify mutations across a person’s entire genetic landscape. Each of us have approximately 20,000 genes in our body responsible for disease-causing mutations. WES tests all of them.

Current genetic testing is responsible for an unnecessary diagnostic odyssey of elimination. Standard testing targets individual genes associated with specific diseases. If a genetic mutation is not found, rare diseases are left undiagnosed and children are subjected to an unnecessary (and often painful) battery of tests. Early WES allows physicians to identify rare genetic disorders in the first year of life. With this early detection, gene therapy will emerge and cures will be discovered. What was once a rare and undiagnosed genetic disorder will be a condition with clinical answers.

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Just after her second birthday our daughter, Susannah, was diagnosed with a rare genetic mutation in her KIF1A gene. She is the only person reported in literature with this mutation and one of approximately 20 children with similar variants in KIF1A. The disease has no name and is referred to as a KIF1A-Related Disorder. Susannah’s disorder carries with it a progressive and degenerative neurological condition. She is a superhero.

Much like alcoholics turn to a bottle, I turned to excessive research when we received Susannah’s diagnosis. One night in September I was on the phone pleading with a biologist in Sweden. His response echoed the countless calls before: he could not care for my daughter. The reason was all too familiar – there has never been a large enough patient pool to conduct a proper clinical study of this rare condition. While listening to him, I searched for answers in a 1,000-page genetics textbook with contents I couldn’t even pronounce, let alone understand. I was overwhelmed and desperate. At that exact moment, I heard Susannah and my five-year-old son, Nat, laughing in the tub with their mother. I closed the book, hung up the phone and cried. Again.

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Parenting a child with special needs requires planning. Logistics in a world of insurance, accessibility, schools and healthcare takes time. The ability to prepare for this, while heartbreaking, is a gift. Newborn screening provides an idea of what to expect in the future and how to give your child the highest-possible quality of life. The reality of Susannah’s rare disease is devastating. The heartbreak would not be any less substantial if we knew about her genetic disorder at birth; however, the quality of her first two years of life would have been better.

If WES had been standard twelve-month screening in 2014 when Congress passed the bill, Susannah would be healthier. At the very least we would be more prepared for what is happening right now. Hundreds of diagnosed KIF1A mutations would already have encouraged research. Clinical studies with therapeutic targets would result in an acceleration of medical discovery; orphan drugs leading to pre-clinical trials would be in development and even gene therapy reversing the implications of Susannah’s disorder would be on the horizon. At the very least, KIF1A Disorder would be recognized as a rare disease in national databases, biobanks with necessary tissue samples and patient registries would be global resources for scientists to drive the quest for a cure. Such an initiative wold yield more KIF1A patients, allowing for larger sample sizes and successful treatment.

If public health policy for children with rare diseases had been a priority for our government in 2014, maybe Susannah would be able to play with her brother on the playground. Maybe Nat wouldn’t cry when he sees his sister trying so hard to run in a body that can only imagine what running feels like.

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We were told 25 de novo (non-inherited) mutations in KIF1A have been reported worldwide. Of those, we located 21 who are under the age of seven. Of those 21, four are under the age of five. We know about these children because they had access to WES and the rare mutation in KIF1A was identified. Hundreds of people are living with undiagnosed disorders caused by the same genetic anomaly our daughter has. These families don’t have access to WES and often don’t even know it exists. If in the first year of life WES was mandatory, hundreds of undiagnosed genetic disorders would now be identified and treatable.

Our beautiful daughter struggled through two years of speech delay, movement disorder, neurological abnormalities and Spastic Paraplegia. She has endured extensive therapy, invasive tests, chronic infection and more. Those two years have been unbearable for us but we’re very fortunate. I have since met parents whose children experienced severe KIF1A-Related Disorders for years without a diagnosis. Most of them suffered through one misdiagnosis after another. I recently met a family that waited 20 years to find a medical explanation for their child’s debilitating, undiagnosed disease. Only last month did they find out about WES, a test that has existed for nearly 10 years.

Susannah isn’t the only KIF1A superhero. We have a whole fleet of genetic superheroes in our corner. If anybody reading this has a child with an undiagnosed disease, call me. Our superheroes are far too humble for me to name them here. Our superhero is a doctor who sends emails making sure we give the kids an extra hug from her. She smiles and asks what Susannah was for Halloween (Wonder Woman, of course) and responds at 2 a.m. when a spastic episode strikes. Our superhero is a social worker who didn’t rest until she found a school for Susannah. Our superhero is a genetic counselor who hugged us on the worst day of our lives.

These superheroes won’t deny any family treatment or testing – that’s rarer than any disease. So, have no fear: the team is in place and they don’t sleep. We know relentless advocates of families with rare genetic disorders. These superheroes will answer the call. These people give undiagnosed children the best possible care.

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WES is typically classified as “experimental” and insurance (including Medicaid and Medicare) rarely covers the test. Instead insurance carriers (again, including Medicaid and Medicare) hemorrhage funds on standard tests targeting single-gene disorders like Cystic Fibrosis and Sickle Cell. If one genetic test comes back negative and the person is still sick, another test is performed. And another. And another. And another until either a disease-causing variant is located and a diagnosis is made – or no mutation is found and the patient goes undiagnosed. This diagnostic process often takes years. Repetitive testing and unnecessary treatment costs exponentially more and takes much longer to accomplish than one WES test. Whole Exome Sequencing is cost-effective, efficient and humane.

WES should not be mandatory at birth; however, if developmental and physical milestones are not met by twelve months of age it is ethically and (after the 2014 amendment passed) legally required. Mandatory Whole Exome Sequencing is the literal application of this law: “To ensure newborn babies with deadly yet treatable disorders are diagnosed quickly.”

In the U.S., for a disease to be considered “rare” it affects fewer than 200,000 people. An estimated 80 percent of rare diseases are caused by genetic mutation. Imagine if 80 percent of rare diseases were identified in the first year of life. Imagine if 160,000 families had the opportunity to plan for a challenging future. It is vital that WES becomes a federally mandated test. When President Obama approved the amendment to the Newborn Screening Saves Lives Reauthorization Act of 2014 Whole Exome Sequencing became our daughter’s right.

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The Newborn Screening Saves Lives Reauthorization Act of 2014 specifically addresses the need for guardian consent before testing on human subjects – in this case babies under the age of one year. WES carries ethical implications that are cause for detailed regulation on consent. A specific policy of consent must be constructed. This is where my argument requires thorough consideration.

WES results will show if a baby is carrying an altered gene that might cause future disease. For example, having a breast cancer gene (BRCA1 or BRCA2) means you are at high risk of developing breast cancer at some point in your life; however, it does not indicate with certainty that you will get breast cancer. In this instance, it should be made clear: WES newborn screening results will not be reported unless extensive genetic counseling is provided and the guardian requests full WES results.

Conversely (using Susannah’s condition as an example) if early WES results show a mutation in the KIF1A gene it must be reported. In this case, immediate clinical action can be taken to treat a baby with a mutation in KIF1A.

The first human genome was completed in 2003 and cost $2.7 billion. Today WES costs under $500. The President’s 2017 Budget provides $82.8 billion in discretionary funding for the Department of Health and Human Services to “expand critical investments protecting health and wellbeing of the American people.”

Surely allocating discretionary funds for WES is exactly what the Health and Human Services Budget aims to accomplish. Yesterday an article was published (Stark et al., Genetics in Medicine 2017) supporting appropriation for Whole Exome Sequencing. Funding WES will save our healthcare system millions of dollars. The average cost per diagnosis using standard genetic testing is $21,099 compared to $3,937 for one single Whole Exome Sequencing test.

Stark et al. concludes “Use of WES early in the diagnostic pathway more than triples the diagnostic rate for one-third the cost per diagnosis, providing strong support for reimbursement as a clinical test.”

As cost continues to decrease, mandatory WES is a necessary federal investment. The amendment is a vital attachment to H.R. 1281, a bill passed in 2014 requiring the Secretary of Health and Human Services to enforce a federal law ensuring newborn babies with deadly yet treatable disorders are diagnosed quickly.

Waiting for Senate to pass a bill requiring Medicaid to cover Whole Exome Sequencing is not an option for me. I cannot wait for people to spread the word about WES. I need every undiagnosed baby tested immediately. I need clinical trials to begin yesterday. Federal regulations making Whole Exome Sequencing part of newborn screening will save the lives of children like Susannah.

I’m not a physician. I’m not a scientist or a lawmaker. I’m a father. If new variants in KIF1A are identified early, I am positive our team of genetic superheroes will find a cure. Maybe Susannah will keep up with her brother on the playground. Maybe she’ll know how it feels to run without falling. One thing is certain: no matter what happens, Susannah will keep picking herself up every single time. We’re the luckiest parents in the world – our kids are superheroes.