A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3

Abstract

Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations.

Building dialogues between clinical and biomedical research through cross-species collaborations

“…Findings from our functional fruit fly studies are transmitted to the clinical sites for real-time discussion of the findings, interpretation of the relevance to the human condition, and designing subsequent animal model studies based on clinical insights. The synchronized bench and bedside investigations between the UDN clinical sites and the MOSC demonstrate great potential for accelerating the genetic diagnosis of complex disorders and determining disease mechanisms in vivo [28–30]. …”

“…This strategy is key to the discovery or co-discovery of the genetic basis of many disorders and understanding the mechanisms of disease. Frequent interactions and collaborations between clinical medicine and biomedical research at the NRI fostered our understanding of several diseases including Fragile X syndrome, Angelman syndrome, Rett syndrome, MECP2 duplication syndrome, myotonic dystrophy, Parkinson’s disease, Alzheimer’s disease, Spinocerebellar ataxia type 1, Friederich’s ataxia, amyotrophic lateral sclerosis, Leigh syndrome, Charcot-Marie-Tooth, other inherited ataxias, neuropathies, lysosomal storage disorders, epilepsies, and syndromic neurodevelopmental disorders [21, 28, 35–42]. …”

“…Another example from our research group of how clinicians are able to connect to basic research scientists through the UDN MOSC to diagnose rare disorders is the discovery that Early B-cell Factor 3 ( EBF3 ) mutations were found in individuals with a unique neurodevelopmental disorder [28]. EBF3 is an atypical helix-loop-helix (HLH) transcription factor associated with many neurodevelopmental processes across multiple model organisms [60].…”

Integration of Drosophila and Human Genetics to Understand Notch Signaling Related Diseases

“…Easily scorable phenotypes such as lethality or sterility can be used as crude assays to determine whether the human protein can function in the fly body. If one observes a complete or partial rescue with a reference (wild-type) human cDNA, one can use this as a reference point to compare how well the variant cDNA functions [418,419]. Further rescue experiments of Notch related phenotypes (e.g.…”

MARRVEL: Integration of Human and Model Organism Genetic Resources to Facilitate Functional Annotation of the Human Genome

“…Hence, a user-friendly open-access web-based resource to curate and synthesize current knowledge and resources from model organisms and human genomics databases is invaluable. [11][12][13] Material and Methods…”