Researchers from Children’s Hospital of Philadelphia (CHOP) have identified a rare genetic variant that causes neurological disorders, including prominent leukodystrophy, in a global study that is the first to characterize the variant’s effects on 11 patients. The study, recently published in the American Journal of Human Genetics, represents a critical first step toward understanding the underlying mechanisms of the disease and providing support for this patient community.
Leukodystrophies are a group of rare, genetic disorders that cause abnormal growth of the white matter in the brain and can lead to a variety of neurodegenerative symptoms that affect movement, speaking, hearing and mental and physical development. While the symptoms of leukodystrophies are well known, many subtypes do not yet have a known genetic cause, and new types of leukodystrophies are identified each year.
The study was prompted by identifying a leukodystrophy patient with no previously described genetic variants associated with the disorder, but with changes in the BLOC1S1 gene. This gene is associated with the BLOC-one-related complex (BORC), which has been linked to other forms of leukodystrophy, so researchers wanted to investigate further.
“We began reaching out to other researchers around the world asking if they saw any other patients who looked similar to the first patient with changes in the same gene, and they said they did,” said study author Carlos A. Dominguez Gonzalez, CGC, a genetic counselor in the Leukodystrophy Center of Excellence at CHOP. “Through a combination of the connections we have made with the global leukodystrophy community and genetic databases, we identified enough patients to determine whether it was that genetic change that was causing these symptoms.”
The study identified seven distinct variants in BLOC1S1 across 11 individuals from seven independent families. These patients presented with early psychomotor delay, low muscle tone, epileptic encephalopathy (EE) and irreversible vision loss, among others, and some affected individuals also had lighter patches of skin and reduced pigmentation in the eyes.
In addition to identifying common symptoms associated with these genetic changes, the researchers also determined some of the underlying biological mechanisms that might lead to leukodystrophy in the patients. Loss of function, or reduced normal activity, of BLOC1S1 leads to more pronounced deficits in the BORC complex, which links them to a group of leukodystrophies that have been described as BORCopathies because of their connections to this particular complex.
“This is an important first step toward improving diagnosis and studying potential treatments,” says Adeline Vanderver, MD, Program Director of CHOP’s Leukodystrophy Center of Excellence. “Our research highlights just how genetically diverse leukodystrophies are. By expanding the spectrum of known disease-causing variants, we’re improving our ability to recognize these conditions and understand how they develop.”
This study was supported by the National Institutes of Health grant U54NS115052, the Intramural Program of the NICHD via grant ZIA HD001607, the Netherlands Organisation for Scientific Research grant 09150172110002, a Chan Zuckerberg Initiative Neurodegeneration Challenge Collaborative Pairs grant, and the Medical Research Future Fund grant ARG76368.
De Pace et al, “BLOC1S1 variants cause lysosomal and autophagic defects resulting in a hypomyelinating leukodystrophy with epileptic encephalopathy.” Am J Hum Genet. Online April 2, 2026. DOI: https://doi.org/10.1016/j.ajhg.2026.02.024.
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Researchers from Children’s Hospital of Philadelphia (CHOP) have identified a rare genetic variant that causes neurological disorders, including prominent leukodystrophy, in a global study that is the first to characterize the variant’s effects on 11 patients. The study, recently published in the American Journal of Human Genetics, represents a critical first step toward understanding the underlying mechanisms of the disease and providing support for this patient community.
Leukodystrophies are a group of rare, genetic disorders that cause abnormal growth of the white matter in the brain and can lead to a variety of neurodegenerative symptoms that affect movement, speaking, hearing and mental and physical development. While the symptoms of leukodystrophies are well known, many subtypes do not yet have a known genetic cause, and new types of leukodystrophies are identified each year.
The study was prompted by identifying a leukodystrophy patient with no previously described genetic variants associated with the disorder, but with changes in the BLOC1S1 gene. This gene is associated with the BLOC-one-related complex (BORC), which has been linked to other forms of leukodystrophy, so researchers wanted to investigate further.
“We began reaching out to other researchers around the world asking if they saw any other patients who looked similar to the first patient with changes in the same gene, and they said they did,” said study author Carlos A. Dominguez Gonzalez, CGC, a genetic counselor in the Leukodystrophy Center of Excellence at CHOP. “Through a combination of the connections we have made with the global leukodystrophy community and genetic databases, we identified enough patients to determine whether it was that genetic change that was causing these symptoms.”
The study identified seven distinct variants in BLOC1S1 across 11 individuals from seven independent families. These patients presented with early psychomotor delay, low muscle tone, epileptic encephalopathy (EE) and irreversible vision loss, among others, and some affected individuals also had lighter patches of skin and reduced pigmentation in the eyes.
In addition to identifying common symptoms associated with these genetic changes, the researchers also determined some of the underlying biological mechanisms that might lead to leukodystrophy in the patients. Loss of function, or reduced normal activity, of BLOC1S1 leads to more pronounced deficits in the BORC complex, which links them to a group of leukodystrophies that have been described as BORCopathies because of their connections to this particular complex.
“This is an important first step toward improving diagnosis and studying potential treatments,” says Adeline Vanderver, MD, Program Director of CHOP’s Leukodystrophy Center of Excellence. “Our research highlights just how genetically diverse leukodystrophies are. By expanding the spectrum of known disease-causing variants, we’re improving our ability to recognize these conditions and understand how they develop.”
This study was supported by the National Institutes of Health grant U54NS115052, the Intramural Program of the NICHD via grant ZIA HD001607, the Netherlands Organisation for Scientific Research grant 09150172110002, a Chan Zuckerberg Initiative Neurodegeneration Challenge Collaborative Pairs grant, and the Medical Research Future Fund grant ARG76368.
De Pace et al, “BLOC1S1 variants cause lysosomal and autophagic defects resulting in a hypomyelinating leukodystrophy with epileptic encephalopathy.” Am J Hum Genet. Online April 2, 2026. DOI: https://doi.org/10.1016/j.ajhg.2026.02.024.
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