Researchers Unlock Genetics of Ultra-Rare Neurodevelopmental Disorder

Rare Daily Staff

Researchers at Ottawa’s Faculty of Medicine have revealed how gene mutations work to cause Borjeson-Forssman-Lehmann Syndrome, an ultra-rare, neurodevelopmental disorder with fewer than 100 reported cases since its first description in the early 1960s.

Borjeson-Forssman-Lehmann Syndrome (BFLS) is an X-linked disorder that’s characterized by seizures, intellectual disability, and behavioral disturbances. Children born with the disease typically exhibit physical symptoms including distinctive facial features and growth defects such as tapered fingers.

But the researchers said the findings open a way to target a larger number of X-linked intellectual disability disorders.

In a study published in EMBO Reports, the authors note the results could have broader impact, potentially pointing to treatment approaches for other rare X-linked neurodevelopmental syndromes.

“The study of rare diseases of neurodevelopmental disorders and cognitive impairments advances our understanding of underlying mechanisms of disease pathogenesis and lays the foundation for the design of novel therapeutics,” said senior author Arezu Jahani-Asl, Canada Research Chair in Neurobiology of Disease, an associate professor in the Department of Cellular and Molecular Medicine, and affiliate investigator at The Ottawa Hospital.

The project started by characterizing PHF6 gene regulation of the genome in the developing cortex of an embryonic mouse brain. The researchers identified a panel of ephrin receptors as direct downstream targets using computational approaches and multiomics.

They then used different mouse models of the disease to establish that they exhibited altered neural stem cells and progenitor populations, as well as deregulation of ephrin receptors, which are proteins involved in a wide range of processes in developing human embryos.

The consequence of this phenomenon, according to Jahani-Asl, is that the “Eph-A” family of receptors are a viable transcriptional target of the PHF6 gene and may “represent a therapeutically exploitable target” for BFLS and other X-linked intellectual disability disorders (XLID).

“The goal is to translate these discoveries into practical applications that could benefit individuals affected by XLID and other cognitive disorders stemming from neural stem cell misregulation,” Jahani-Asl said.