A research team at The Hospital for Sick Children (SickKids) has identified variants in the gene known as CLDN5 as the genetic cause of a rare neurogenetic syndrome.

In the study published in December in Brain, the team describes how  results from whole exome sequencing, a technique that sequences all protein-coding regions of the genome, were used to identify variants in the CLDN5 gene in 15 unrelated patients with seizures, microcephaly, developmental delay and other neurological features. They then confirmed, by modelling the CLDN5 genetic variants in zebrafish, that they were the cause of the patients’ symptoms.

Led by Dr. Jim Dowling, Staff Clinician and Senior Scientist in the Genetics & Genome Biology program, and Dr. Rosanna Weksberg, Clinical Geneticist and Senior Associate Scientist in the Genetics & Genome Biology program, the researchers also used brain imaging to uncover a specific pattern of brain calcifications in all 15 cases, with the assistance of Dr. Susan Blaser, a Neuroradiologist at SickKids.  These brain findings have the potential to inform earlier clinical diagnosis for people with the condition.

“At SickKids we see many patients with undiagnosed genetic disorders. Identifying the underlying molecular basis of these disorders provides us with an opportunity to learn important lessons from these patients that will enhance our understanding and treatment of rare disorders,” explained Dowling and Weksberg. “This work is an important example of the value of Precision Child Health, a movement at SickKids to deliver individualized care based on each child’s unique characteristics, including their genetic profile.”

Learn more about this discovery and what’s next for the research team from first authors Dr. Ashish Deshwar, a resident in Medical Genetics and Genomics, and Cheryl Cytrynbaum, Genetic Counsellor and Project Investigator in the Genetics & Genome Biology program.

How did you identify this new disorder?

“We first identified a variant of interest in the CLDN5 gene in one of our patients at SickKids using whole exome sequencing through The Centre for Applied Genomics (TCAG),” says Cytrynbaum. “Our patient had microcephaly (a condition where a baby’s head is smaller than usual), visual impairment, seizures and developmental delay, which led us to suspect an underlying genetic cause.”

"Once we identified a variant in the CLDN5 gene, we connected with clinicians from around the world who had patients with similar clinical features as well as variants of interest in the CLDN5 gene,” explains Deshwar.  “After a series of studies, including modelling the genetic changes in zebrafish, we found that these unique genetic changes in CLDN5 were the cause of the clinical features in this select group of cases.” 

What does this research mean for people with this CLDN5 related disorder and their families?

“This research provides a genetic diagnosis for these children and families who have experienced years of uncertainty with respect to a primary cause for the children's medical issues,” says Cytrynbaum.

“Going forward, this knowledge could help facilitate earlier diagnosis for children presenting with this disorder, which can now be predicted based on findings from brain imaging and then confirmed by genetic testing. Understanding the molecular basis of the condition is an important first step in identifying avenues for potential therapeutics.” 

What are the next steps for this research?

“We want to go beyond diagnosis and identify exactly how these variants affect the CLDN5 protein and better understand their role in disrupting the function of the blood-brain barrier,” says Deshwar. “We also hope to use this information to identify and test potential therapies.”

This research was funded by the Rare Diseases: Models & Mechanisms Network and supported by the SickKids Zebrafish Genetics and Disease Models Core Facility.