Genetic cause behind novel DEE syndrome discovered

Autism and epilepsy are two highly prevalent conditions that fall under the umbrella of neurodevelopmental disorders (NDD), which affect 1–3% of the world’s population just in terms of cognitive disabilities.


Image Credit: SewCream/

Epilepsy, delayed development, or loss of developmental skills are characteristics of developmental epileptic encephalopathies (DEE), a subtype of NDD. Although the prevalence of DEEs is unknown, studies suggest that 1 in 2100 births each year are affected by single-gene epilepsies.

A novel DEE syndrome was recently linked to changes in the Eukaryotic Initiation Factor 4A2 (EIF4A2) gene, according to research from the labs of Dr Hsiao-Tuan Chao, assistant professor at Baylor College of Medicine (BCM) and investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, and Dr Pankaj Agrawal, professor at Harvard Medical School and Boston Children’s Hospital.

The new finding, which was reported in the American Journal of Human Genetics, offers the first experimental proof that changes affecting EIF4A2 are causal in human disease.

Identifying individuals with a new neurodevelopmental disorder

A virtual tool called MatchMaker Exchange, which was introduced in 2013 to act as an integrated platform for clinicians and researchers all over the world to exchange phenotypic and genotypic data and significantly speed up genomic discovery, enabled the study’s international collaboration.

Using this tool, Dr Anna Duncan, an instructor in Dr Agrawal’s lab and co-first author of the study, identified about 15 individuals from 14 families who had structural changes in the brain (as observed by MRI imaging) and similar clinical presentations comprising global developmental delays, poor muscle tone, speech impairments, and epilepsy. They found these individuals carried extremely rare spontaneous mutations in one or both copies of EIF4A2.

Dr Hsiao-Tuan Chao, Assistant Professor, Baylor College of Medicine

A protein called an ATP-dependent RNA helicase, which is produced by the EIF4A2 gene, controls the ribonucleic acid’s three-dimensional (3D) structure (RNA). All tissues express the EIF4A2 protein, which controls how proteins are translated.

It is a member of the DEAD-box family, a collection of 50 closely related proteins, many of which control protein translation, a critical molecular mechanism that transforms messenger RNAs into the corresponding proteins. EIF4A2 has been linked to intellectual disability in previous studies and has been implicated as being essential for brain development.

Using fruit flies to understand how mutations in elF4A cause this syndrome

Study co-first author Dr Maimuna Sali Paul, a postdoctoral fellow in the Chao lab, and Dr Chao meticulously examined human EIF4A2 variants and its fruit fly counterpart, elF4A, with which it shares significant sequence similarity, to determine whether these gene variants are accountable for the neurological symptoms seen in these patients.

They discovered four variations of EIF4A2 that affected conserved residues in the fly gene eIF4A and were predicted to affect the human EIF4A’s 3D structure and its interaction with RNA by molecular modeling data.

In the fruit fly, overexpression of these EIF4A2 variants caused many behavioral and developmental defects, including motor defects, improper development of the eyes, wings, and peripheral nervous system organs like bristles, which was a blatant sign of their toxicity, according to Dr Paul.

The functional effects of the human EIF4A2 variants were also studied by Dr Paul using the knowledge that complete eIF4A loss was lethal at the fruit fly embryonic stages, whereas reducing its levels from specific tissues was lethal in either the embryonic or pupal stages.

Most importantly, when we overexpressed the wild-type human EIF4A in the eyes of the flies lacking this gene, we were able to completely ‘rescue’ the pupal lethality and restore the normal lifespan of these flies. However, overexpression of one disease-causing variant resulted in a weak/partial rescue while the others were unable to rescue the lethality—a clear indication of the essential role they play during development.

Dr Maimuna Sali Paul, Study Co-First Author and Postdoctoral Fellow, Baylor College of Medicine

Dr Chao added, “Consistent with this study, our lab had previously found that loss of a kinase, EIF2AK2 which regulates downstream protein complexes involved in protein translation also causes similar neurological impairments.

He further stated, “Thus, our findings in this study underscore the critical role of balanced regulation of protein translation for brain development and maintenance of function in neurons and glia. These findings reveal EIF4A2 as a previously unrecognized cause of a novel developmental epilepsy syndrome.

Journal reference:

Paul, M, S. et al. (2022). Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy. American Journal of Human Genetics.


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