Racing to solve rare diseases

Two clinicians at Yale Child Study Center, Fred Volkmar, MD, and Alexander Westphal, MD, PhD, provided Abha Gupta, MD, PhD, support during a preliminary study of 15 families affected by childhood disintegrative disorder, which revealed neurobiological differences between it and other forms of autism.

During postdoctoral training, Gupta’s general autism research had not included meeting any individuals or families affected by childhood disintegrative disorder. The collaboration with Volkmar and Westphal gave Gupta, associate professor of pediatrics, a firm footing to push her research forward. Her initial encounters with patients had a lasting impact.

Childhood disintegrative disorder (CDD), or severe regressive autism, typically affects one or two in 100,000 children. It is characterized by a relatively late loss of acquired skills in social, language, and motor functioning. “These children have experienced normal development, and it sometimes seems like the regression is overnight,” Gupta said. “When development stabilizes, they are often severely impaired.”

Gupta and her colleagues could find no clear signal of the cause of CDD regression. “About three-fourths of the kids have a striking period before the regression when they are very agitated or upset,” Gupta said. “The disturbing thing about CDD is wondering if younger kids feel that stress, and they cannot articulate it.”

Gupta’s immediate goal is to recruit 50 families to obtain funding for whole genome sequencing and imaging studies. Gupta has received patient referrals from Jennifer Bain, MD, at Columbia University. Sally Ozonoff, MD, at UC Davis, has analyzed family home videos to document the timing and nature of CDD regression.

Funding for such projects, however, has become more difficult to secure during the last few years since CDD was removed from DSM-5 and placed into the broader category of autism spectrum disorder.

Collaboration, mentorship, and institutional opportunity in the Department of Pediatrics at Yale School of Medicine (YSM) are crucial to rare disease research. By definition, a rare disease does not affect many people, and it can be difficult to justify directing scarce or precious resources away from efforts to treat a more widespread condition.

At YSM, however, abundant institutional capabilities exist to support research. The Department of Pediatrics and Yale Child Study Center boast a longstanding tradition of inquiry into obscure childhood ailments that can have catastrophic consequences later in life. Knowledge and relationships that go back decades help shape research today.

The late Ruth Whittemore, MD, a pediatric cardiologist, authored papers as early as 1987 addressing genetic factors of congenital heart disease. With that foundational research in hand, Martina Brueckner, MD, professor of pediatrics (cardiology), has witnessed a striking recent change in available data on the causes of congenital heart disease.

“The field of what causes congenital heart disease has substantially changed during the last 12 to 15 years,” Brueckner said. “When I was training, we were told it was multifactorial. If a child was born with a heart defect, parents would be blaming themselves.”

Current research suggests that most of those cases of heart disease are either influenced by genetic factors or are entirely caused by genetic mutations. Richard Lifton, MD, who served as chair of the Department of Genetics at Yale from 1998 to 2016, helped to develop genomic approaches to the diagnosis of rare diseases. “Some of the first papers using exome sequencing to make genetic diagnoses came out of Yale,” Brueckner said. “The Yale Center for Genome Analysis has been incredibly generous about sequencing all of our congenital heart disease samples. After the Human Genome Project, we were first able to do a large-scale genomic analysis of congenital heart disease patients around 2010.”

When the National Institutes of Health started pumping funding into congenital heart disease research a dozen years ago, Lifton and Brueckner turned out to be in the right place at the right time. That enabled Yale and a handful of other institutions throughout the United States to develop a large genomic and phenotypic database of patients through their NIH-funded group, the Pediatric Cardiac Genomics Consortium. The consortium has recruited 15,000 congenital heart disease patients. The Yale Center for Genome Analysis has been able to do exome sequencing on a large number of patients. “Hopefully by the end of 2023, we will have sequence data on 14,000 of the 15,000 patients,” Brueckner said. “Now that you have so many patients and real data, we have learned that a lot of congenital heart disease does have clear-cut genetic causes.”

Being able to return test results more quickly to rare disease patients has provided a boost for Mustafa Khokha, MD, professor of critical care pediatrics and of genetics, and his peers. Khokha is also the director of the Pediatric Genomics Discovery Program, which seeks to discover the genes that cause childhood diseases. “Sometimes it could take years to see results because these patients are rare,” Khokha said. “Returning that result to patients … nothing is more motivating than that.”

As the cost of whole genome sequencing has gradually dipped to about $200, opportunities to examine small patient populations have increased.

“That [low cost] is important—it is the number one boost to innovation,” Khokha said. “If we see a patient who we think might have a genetic disorder, there is very little hesitation from us to sequence the patient because there isn’t a cost barrier.”

Birth defects are a leading cause of infant mortality, accounting for 20% of infant deaths in the United States, according to the Centers for Disease Control and Prevention. “Even though these disorders are very rare molecularly … overall, they are the biggest problem in pediatrics,” Khokha said.

Whether the diagnosis is CDD, congenital heart disease, or a host of other rare diseases, medical scientists at YSM are applying existing rare disease research on a broader scale. “Rare diseases do not just impact one patient,” Khokha said. “They have a tremendous impact on general biology.” 

Brian Hudgins is a first-time contributor to Yale Medicine Magazine.