New research identifies promising genetic target

image: Mr. Hashim Raza, assistant professor at the KU Life Span Institute and the Doctoral Program in Children’s Language at the College of Liberal Arts and Sciences, and Erin Andres of the Doctoral Program in Children’s Language at KU
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Credit: Drew Rosdahl

LAWRENCE — A study by the University of Kansas recently published in the peer-reviewed journal brain science identifies a new genetic target linked to specific language disorders (SLI).

The discovery of BUD13 for future biological investigation of language acquisition offers researchers the potential to better diagnose and understand communication disorder.

SLI slows the development of language skills in children who do not have clear intellectual, sensory, neurological, or emotional deficits. While the causes of SLI are still unknown, researchers in the field believe that genetic factors play a key role. According to the most recent research in the field, 10% of kindergarten children in the United States have SLI.

“SLI is a neurodevelopmental disorder that normally appears in children as they begin their language acquisition,” said co-author M. Hashim Raza, assistant professor at the Life Span Institute and Child Language Doctoral Program at the College of Liberal Arts & Sciences at KU. “It can be difficult to identify these children, but they may have problems with speech and learning grammar and not be very talkative – but they are otherwise typical children. If we talk about their nonverbal IQ level, they are in the average range, and sometimes we see that their nonverbal IQ level is even higher than average people.

Because SLI can be difficult to diagnose, researchers sought to find biological markers that could lead to earlier treatment and intervention for children with the impairment.

“It’s not very easy to identify these individuals,” Raza said. “They really have to go through a lot of assessments – but if there was some sort of genetic marker, we could find this problem at a very early stage in life and design interventions to reduce the complexity of this disorder. This problem persists throughout their lives. Growing up, we saw these people face social and relationship issues, and struggle to succeed in their careers. This problem can therefore persist into adulthood. But it can be manageable at first if these people are identified and diagnosed.

Raza’s brain science study focused on a single family (dubbed the “489 family”) with 10 children, seven of whom have SLI. The family is part of a larger ongoing longitudinal study of people with ILS and their family members, led by KU Fred & Virginia Merrill Professor Emeritus of Advanced Studies Mabel Rice and her Language Acquisition Studies Laboratory in collaboration with Raza and his Human Molecular Genetics Laboratory.

Raza’s co-authors on the paper, in addition to Rice, were Erin Andres of KU’s Child Language PhD program; Kathleen Kelsey Earnest of KU’s Language Acquisition Studies Laboratory; and Cuncong Zhong, assistant KU professor in the Department of Electrical Engineering and Computer Science.

“We use what’s called a ‘family-based study’ because in family studies we don’t need thousands of individuals,” Raza said. “We call them informative families so that we can conclude our genetic findings based on how many people in these families are affected and unaffected. We used next-generation sequencing methods and bioinformatics tools to focus on potentially pathogenic and co-segregating rare genetic variants in our baseline family. Once a potential gene target is identified, we sequence the entire gene in other people with ILS to confirm pathogenicity.

Andres, a GRA in Raza’s lab, used these sequencing methods to study SLI in the 489 family. The results implicated the novel genetic target, BUD13, for future biological investigation of language acquisition.

The KU researcher said studies using a family-based approach, like the one in this research effort, are relatively rare in the literature, although genetic relationships within extended families add unique power to the study. .

The rare variant BUD13, changing the amino acid arginine to glutamine, observed in the 489 family, is expected to be damaging by several computational models. Co-segregation of variants in affected family members prompted follow-up analysis of the gene in other cases of SLI.

Next, the researchers sequenced the coding regions in another 175 people with IBS from Rice’s larger study to confirm a role for BUD13 in the communication disorder.

“We identified nine additional rare variants of the BUD13 gene in 15 individuals with SLI, indicating that BUD13 is a strong candidate for SLI,” Raza said.

“Individuals in the longitudinal survey were also comprehensively assessed behaviorally with multiple measures of nonverbal intelligence, language, reading, and nonverbal memory, Raza said. “The study used precise criteria to define SLI status, including children as probands if they had low standardized omnibus language scores, but excluding children with low nonverbal IQ scores.”

The delayed but similar trajectory of language development in children with ILS compared to their age-matched, typically developing peers supported the epigenetic hypotheses developed by Rice – in particular, that regulatory genes and epigenetic factors are involved in SLI expression during early development. The new gene target, BUD13, could support these hypotheses because the BUD13 protein processes RNA and creates a diversity of proteins from the same gene in a tissue-specific way, affecting the fate of other genes. The discovery of BUD13 supports the power of a family-based approach in studying complex behavioral traits, such as SLI.

According to the KU researchers, further support for BUD13 as a target gene for language acquisition comes from evidence from two other recent studies: 1) a large deletion spanning BUD13 was observed in an individual with neurodevelopmental (Servetti et al., 2021); and 2) an animal model with a loss-of-function mutation in BUD13 showed a severe neuronal phenotype, suggesting that BUD13 has a role in neuronal functions (Fernandez et al., 2018).

“Based on genetic evidence from our family study and previous reports, we suggest that BUD13 regulates the expression of other genes, primarily neuronal genes, and is a novel key target gene for SLI,” Raza said.

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