A team of researchers at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital recently completed a study that provides an answer to a puzzling question: why some patients with Early B-Cell Factor 3 (EBF3) gene variants develop symptoms that are significantly more severe than those experienced by other individuals with the EBF3-related autism spectrum and neurodevelopmental disorders.
Dr. Hsiao-Tuan Chao, a pediatric neurologist at Texas Children’s Hospital, a neuroscientist at the Duncan NRI and an assistant professor at Baylor College of Medicine (Baylor), was the principal investigator, and the study was published in the Annals of Neurology.
By combining a comprehensive meta-analysis of the medical literature with extensive genotype-phenotype (i.e., gene mutation type-symptom) analysis in the largest cohort of individuals diagnosed with EBF3-related disorders so far, Dr. Chao and her team discovered that patients with EBF3 gene variants affecting a critical region — zinc finger domain (ZNF) of the encoded transcription factor protein — suffer from a more severe subtype of EBF3-related autism spectrum and neurodevelopmental disorders.
The EBF3 gene encodes an evolutionarily conserved member of the Collier/Olf/EBF-(COE)-transcription factor family that regulates multiple neurological and non-neurological developmental processes. Loss of one functional copy of EBF3 causes the disorders known as 10q26-deletion syndrome and hypotonia, ataxia and delayed development syndrome (HADDS). Dr. Chao and other researchers from the Undiagnosed Diseases Network and the Duncan NRI, along with other collaborators, co-discovered HADDS in 2016.
“By systematically collating clinical information from the patients diagnosed with HADDS and using computational methods to uncover underlying associations between the precise nature and molecular location of the mutations with the severity of the disease symptoms, our team now has come up with a refined understanding of this condition, which equips physicians to predict the clinical course of the disease for each patient,” said Dr. Chao.
Shortly after the initial gene discovery of EBF3-related HADDS, Dr. Chao opened the world’s first EBF3-disorders-focused clinic at Texas Children’s Hospital and, along with Texas Children’s physician and geneticist Dr. Michael Wangler, have evaluated the largest number of individuals with this condition at a single institution. Although the discovery of a monogenic disorder associated with EBF3 gene alterations is fairly recent, increasing evidence gathered within this short time suggests that EBF3-related autism spectrum and neurodevelopmental disorders may be more common than previously recognized, with EBF3 gene alterations identified as the cause in one in 1,200 individuals with neurodevelopmental disorders.
As Dr. Chao and her team evaluated more individuals with EBF3-related disorders, they were puzzled by the fact that some showed subtle symptoms, while others struggled with severe motor limitations and comorbid neuropsychiatric conditions such as anxiety, autism or attention deficit hyperactivity disorder (ADHD).
EBF3-related disorders were identified just five years ago, so the full spectrum of symptoms and molecular links between the symptom profile and disease severity had not been explored prior to this study.
“The comprehensive characterization of the phenotypic spectrum with algorithmic prediction and functional validation in fruit flies and cell culture was instrumental in making these discoveries,” said first author Cole Diesseroth, a medical student in the Chao lab who is enrolled in Baylor’s dual-degree Medical Scientist Training program. “Together, these approaches revealed the critical role of the ZNF in EBF3’s regulation of developmental processes and the relationship to disease severity.”
The findings of this study will help clinicians in predicting the potential trajectory of the disease and prognosis for each patient diagnosed with EBF3-related autism spectrum and neurodevelopmental disorders. They also will provide the foundation for future mechanistic studies on EBF3-related disorders and will facilitate the development of targeted and personalized therapies for different sub-populations of affected individuals based on molecular findings.
“The quantitative phenotypic and disease severity assessment algorithms developed in this study have the potential for broad applicability across many human neurodevelopmental disorders, including autism spectrum disorders, and can lead to better diagnostic and prognostic predictions as well as new targeted therapies for those conditions,” said Dr. Chao.
Others involved in the study were Vanesa Lerma, Christina Magyar, Jess Pfliger, Aarushi Nayak, Nathan Bliss, Ashley Lemaire, Vinodh Narayanan, Christopher Balak, Ginevra Zanni, Maria Enza Valente, Enrico Bertini, Paul Benke and Michael Wangler. They were affiliated with one or more of the following institutions: Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Baylor College of Medicine, Case Western Reserve University, Texas A&M University, University of California San Diego, University of Pavia, Bambino Gesu Children’s Hospital, Joe DiMaggio Children’s Hospital and McNair Medical Institute. The study was supported by the National Institutes of Health, the McNair Medical Institute at The Robert and Janice McNair Foundation, Burroughs Wellcome Fund, Mark A. Wallace Endowment, the Child Neurology Society and Foundation, Baylor College of Medicine Medical Scientist Training Program, the 2021 Child Neurology Foundation Neurodevelopmental Disabilities Summer Research Scholarship, The Gordon and Mary Cain Foundation and Annie and Bob Graham, Autism Science Foundation, the European Reference Network for Rare Neurological Diseases and the Italian Ministry of Health.