Genetic Cause Identified for Previously Unrecognized Developmental Disorder

Associated features seen in these individuals include congenital hypotonia, structural central nervous system (CNS) malformations, ataxia, and genitourinary abnormalities.

The team used whole exome sequencing, a laboratory technique that allows the identification of all the genes in an individual's genome. In the patients, they identified two new variants of the gene EBF3 that were not present in the patients' parents. Mutations of EBF3 are rare in the general population but more common in a population of individuals with autism spectrum disorders and intellectual disability. 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. Their 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 aristaless-related homeobox (ARX)-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations.

Hsiao-Tuan Chao, MD, PhD, the lead author of the study said, “The gene is known to be essential for normal development of the nervous system. It is one of the key factors involved in how neurons develop and connect with each other, but has not been studied in detail. In animal models, mutations that cause the gene to lose its function result in death of the embryo. EBF3 had never before been associated with a disease.” The study was published on December 22, 2016, in the American Journal of Human Genetics.

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