Uncovering the genetics of learning disabilities

In classrooms across the United States, five to 10 million children struggle with dyslexia. While offering intervention strategies in grades 1 through 3 can drastically improve the trajectory of a student’s education, the window for effective intervention is narrow. That makes early and accurate screening key. Now, researchers are discovering clues in our genes that could speed early assessment of the risk of dyslexia.

For several decades, Jeffrey Gruen, MD, professor of pediatrics (neonatology) and of genetics, has been studying the genetics of learning disabilities like dyslexia. Now, he’s director of the new Yale Program for Learning Disability Research, which brings together faculty and students across the university to tackle this common problem. Through a cuttingedge clinical trial called the New Haven Lexinome Project (NHLP), the program also seeks to uncover the underlying neuroscience of disabilities.

“Most people recognize that learning disabilities run in families, but they often don’t make the connection that it’s genetic,” said Gruen. “And so in the last 20 years, we’ve been identifying those genes and the genetic variants that seem to be associated with prominent learning disabilities.”

Fifteen percent of students around the world suffer from a learning disability, including delayed onset of speech [specific language impairment], verbal trait disorder, dyscalculia [math disability], and attention deficit disorders. One of the most common learning disorders is dyslexia, or difficulty in learning to read. A widely held misconception about disorders like dyslexia, said Gruen, is that they are associated with lower intelligence.

“There are smart people around the world who have high IQs and are incredibly functional, but have a really hard time with reading,” he said. “There have been surveys of Fortune 500 CEOs, for example—they report a much higher prevalence of dyslexia than the general population.”

Left untreated, dyslexia can hinder students’ education, cause low self-esteem, and pose obstacles to meeting their potential as they grow older. Intervention at any age can provide great benefit to struggling students, but treatments are most effective when implemented early. About 75% of first- through third-graders, for example, could be reading at their grade level two years after the completion of a quality intervention program. However, about half of students with dyslexia aren’t identified until high school or later. For this group, response to intervention drops to 25%.

Our current education system has what Gruen calls a “wait-tofail model.” Around the end of first grade, students with dyslexia begin to fall behind their peers as they face a more challenging curriculum. These students don’t begin to receive treatment until they are already struggling; and even with intensive and early intervention, the learning gap never fully closes.

“Children with dyslexia are smart. They can hide their struggle, and you won’t necessarily see it until they are challenged with a complex curriculum,” said Gruen. “And with the wait-to-fail model, they never catch up. This [gap] affects them obviously in their academic careers, but also in life.”

In September 2021, in collaboration with colleagues including Eugene Shapiro, MD, professor of pediatrics (general pediatrics) and of epidemiology (microbial diseases), and Clifford Bogue, MD, the Waldemar Von Zedtwitz Professor of Pediatrics and chair of the department, Gruen launched the Yale Program for Learning Disability Research.

This multidisciplinary program spans the fields of neuropsychology, biostatistics, education, neuroimaging, and genetics. It has several goals, including uncovering the neuroscience underlying learning disabilities; educating school staff and pediatricians on the role of genetics; and advocating for policies that support early intervention. “Our mission is to harness the broad expertise of faculty and students from across the university to study learning disabilities in these core areas,” said Gruen.

The centerpiece of the program, he said, is the NHLP. From 2013 to 2021, Gruen’s team conducted a longitudinal study of 492 typically developing elementary schoolers across 32 New Haven public schools. The students were enrolled in first grade and followed through fifth grade. The researchers conducted whole-genome sequence analysis; assessments three times per school year on reading, language, and executive function; and for some students, serial functional MRIs. Through generating a dataset based on the seven-year clinical trial, Gruen hopes to better understand how genetic variations affect intervention outcomes.

“Think of the New Haven Lexinome Project as the data pipeline for the Yale Program for Learning Disability Research,” said Gruen. “Our current group of graduate students and postdocs are working now to analyze it.”

Most states currently offer universal evidence-based screening for dyslexia, said Gruen, though none offered genetic screening as of 2022. Through research, he hopes to promote genetic screening as a way to assess dyslexia risk early. This approach could enable parents to screen their children as early as infancy, and allow atrisk children to receive evidencebased intervention before they fall behind in school.

“It’s really important that we translate our discoveries about genetics in the lab into something that’s actionable and useful for schools,” said Gruen. “We hope to get states and regions to include genetic screening in their learning disability screening so that kids can be identified early, when intervention really works the best.” —Isabella Backman

A pillar of pediatric research

When Eugene Shapiro, MD, professor of pediatrics (general pediatrics) and of epidemiology (microbial diseases), graduated from Yale College in 1970 (Branford College), the trajectory of his life looked very different from what it later became. A genial and quick-witted storyteller, Shapiro (“Gene” to his friends) had majored in English. He wrote his senior thesis on D.H. Lawrence; he was going to study, teach, or write.

He did something else instead —he started to take premed classes, hoping to attend medical school. He applied to and was accepted by the University of California, San Francisco (UCSF), and completed his MD there in 1976. While there, he met his wife, who became an accomplished Ob/Gyn clinician. They matched together to Pittsburgh, and did their residencies together. Shapiro and his wife had their first child during their residencies—and she may very well have been the first woman to give birth during an Ob/Gyn residency, he added. It was during Shapiro’s years in Pittsburgh that he developed an interest in pediatric infectious diseases.

“My first mentor at Pittsburgh was Ellen Wald, MD. She’s currently chair of the Department of Pediatrics at the University of Wisconsin, Madison. I was able to observe her methods and diligence, and that taught me a lot about how to carry out successful research projects,” said Shapiro.

The couple’s next stop was New Haven, where Shapiro secured a fellowship at Yale School of Medicine through the Robert Wood Johnson Clinical Scholars Program (now the National Clinician Scholars Program). This interest, together with a desire to alleviate children’s suffering, has guided his professional career ever since.

“The RWJCS fellowship helped me refine a lot of what I’d seen in Pittsburgh,” said Shapiro. “It was where I received my first grant; I applied while still a fellow for a National Institutes of Health (NIH) grant to look at the effectiveness of pneumococcal polysaccharide vaccine. I joined the Yale School of Medicine (YSM) faculty in July, and had the grant funded in September.”

The body of work for which Shapiro is probably best known by the public, however, began accidentally. During a general pediatric clinic, a parent called in because her child had been bitten by a tick. In the process of deciding what to do, Shapiro and the residents he was supervising discovered that there had been relatively little published on the subject at that time.

“The original research on Lyme disease was carried out by Allen Steere, MD, here at YSM,” said Shapiro. “But there were a lot of questions that still needed answers. We came up with a randomized clinical trial of antibiotic prophylaxis for tick bites. That’s how I first became involved with Lyme disease.”

Quoted in dozens of articles and featured on broadcast media on the subject in the late 1990s and early- to mid-2000s, Shapiro saw both the positive and negative sides of publicity. He was invited to share his thoughts and expertise with the World Health Organization, the NIH, the Food and Drug Administration, and other groups. Unfortunately, he experienced some backlash from the same groups that have become prominent in the last few years—“anti-vaxxer” and science-skeptic movements facilitated by social media and misinformation.

“People get worried when they’re sick. Doctors and scientists don’t always have the answer, or an answer people want to hear. During moments of grief, people can be incapable of hearing certain answers—such as ‘we don’t have an answer for your specific problem,’ ” Shapiro said.

Shapiro is proud of his success at establishing big-picture research projects during his decades at Yale, including helping begin the prestigious Clinical and Translational Science Award program (CTSA), and his early involvement with Yale’s Investigative Medicine Program, of which he is deputy director. He is co-director for education with the Yale Center for Clinical Investigation (YCCI), which houses the CTSA and plays an important role in advancing young scientists’ careers. YCCI has also worked to recruit a diverse group of subjects for clinical trials to ensure that the trials’ findings are as representative as possible.

“Over the years I’ve mentored, trained, or taught hundreds of students, fellows, and junior faculty,” Shapiro said when asked about his impact as a faculty member. “From research projects to grant-writing programs to residencies, I’ve been incredibly fortunate to connect with so many physicians and PhD scientists.”

The culture of collaboration and cooperation that’s part of YSM’s institutional DNA has, according to Shapiro, played a key role in his success, both in terms of research and by connecting him with so many investigators. “A lot of the people I helped train or mentor as fellows or residents are young faculty themselves now, or more senior,” Shapiro said. “That’s one of my greatest pleasures: to see those people with whom I worked come into their own as scientific leaders.”

Although medicine may seem distant from Shapiro’s undergraduate degree, many of his professional achievements have revolved around successfully crafting narratives, from grant-writing to institutionbuilding. It turns out that having a background in literature isn’t as detached from science and medicine as one might think. —Adrian Bonenberger