Researchers at Children’s Hospital of Philadelphia (CHOP) have found that in rare instances, variants responsible for SYNGAP1-related disorders – a group of disorders characterized by developmental delay and often associated with epilepsy – can be inherited from a parent, which could help influence family planning, genetic variant interpretation, and other aspects of clinical care. The findings were recently published online by the journal Epilepsia.
SYNGAP1-related disorders are caused by variants in the SYNGAP1 gene. Most individuals with SYNGAP1-related disorders have epilepsy that begins in early childhood. Nearly all children with SYNGAP1-related disorders have some degree of developmental delay and cognitive impairment, which typically ranges in severity from moderate to severe. They can also have behavioral differences including autism spectrum disorder.
Most cases of SYNGAP1-related disorders are caused by de novo genetic variants, meaning that they occurred spontaneously in the child and were not inherited from either parent. However, in the course of charting the natural history of SYNGAP1-related disorders, the team at the Epilepsy Neurogenetics Initiative (ENGIN) at CHOP, identified some rare cases in which the variants responsible for the disease were found in multiple people in the same family.
“We realized that in some instances, people with SYNGAP1-related disorders went on to have children and were only diagnosed when their child was diagnosed,” said first study author Alicia Harrison, a genetic counselor with ENGIN at CHOP. “While inherited variants are not the norm for SYNGAP1-related disorders, understanding these rare cases will help us provide better counseling to parents who wish to have another child following a SYNGAP1 diagnosis, as well as guide how we classify genetic variants in familial cases. Accurate variant classification in SYNGAP1 will be increasingly important as we move forward with developing new therapies for these patients.”
The study reported on eight total individuals among three families with inherited, protein-truncating variants in the SYNGAP1 gene. In two of the families, the patient inherited the variant from a heterozygous parent who had symptoms of SYNGAP1-related disorders themselves. In the third family, the variant was inherited from a mosaic parent, meaning that the parent had only a small percentage of cells affected by the variant and did not have any symptoms.
The study also reported on two families with missense variants of uncertain significance, meaning that the variant causes an amino acid substitution, rather than shortening the protein, which can affect how the resulting protein functions. However, more work is needed to determine the clinical significance of these variants.
Study participants were identified through the SYNGAP1 ProMMiS natural history study, conducted by the Center for Epilepsy and Neurodevelopmental Disorders (ENDD) at CHOP and Penn Medicine. This ongoing work is aimed at recruiting as many individuals with SYNGAP1-related disorders as possible to track the progression of symptoms in this condition over time and set the stage for eventual clinical trials.
“In conducting this study, we are meeting a large number of families with SYNGAP1, and as a result, we are making additional discoveries like this one that we did not expect,” said senior study author Jillian McKee, MD, PhD, an ENGIN epileptologist who specializes in neurogenetic disorders at CHOP. “The familial variants we identified may be rare, but these ‘edge cases’ can provide valuable insight into the spectrum of symptoms and their genetic causes.”
This study was supported by the Center for Epilepsy and Neurodevelopmental Disorders (ENDD), the National Institute for Neurological Disorders and Stroke grants R01 NS127830-01A1, R01 NS131512-01 and K02 NS112600, the American Epilepsy Society, Pediatric Epilepsy Research Foundations and the SynGAP Research Fund through a Research Training Fellowship for Clinicians, and the American Academy of Neurology, the Epilepsy Foundation and the American Brain Foundation through the Susan Spencer Award.
Harrison et al, “Familial SYNGAP1 variants define the boundaries of a complex neurodevelopmental disorder with epilepsy.” Epilepsia. Online May 23, 2025. DOI: 10.1111/epi.18469.
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Researchers at Children’s Hospital of Philadelphia (CHOP) have found that in rare instances, variants responsible for SYNGAP1-related disorders – a group of disorders characterized by developmental delay and often associated with epilepsy – can be inherited from a parent, which could help influence family planning, genetic variant interpretation, and other aspects of clinical care. The findings were recently published online by the journal Epilepsia.
SYNGAP1-related disorders are caused by variants in the SYNGAP1 gene. Most individuals with SYNGAP1-related disorders have epilepsy that begins in early childhood. Nearly all children with SYNGAP1-related disorders have some degree of developmental delay and cognitive impairment, which typically ranges in severity from moderate to severe. They can also have behavioral differences including autism spectrum disorder.
Most cases of SYNGAP1-related disorders are caused by de novo genetic variants, meaning that they occurred spontaneously in the child and were not inherited from either parent. However, in the course of charting the natural history of SYNGAP1-related disorders, the team at the Epilepsy Neurogenetics Initiative (ENGIN) at CHOP, identified some rare cases in which the variants responsible for the disease were found in multiple people in the same family.
“We realized that in some instances, people with SYNGAP1-related disorders went on to have children and were only diagnosed when their child was diagnosed,” said first study author Alicia Harrison, a genetic counselor with ENGIN at CHOP. “While inherited variants are not the norm for SYNGAP1-related disorders, understanding these rare cases will help us provide better counseling to parents who wish to have another child following a SYNGAP1 diagnosis, as well as guide how we classify genetic variants in familial cases. Accurate variant classification in SYNGAP1 will be increasingly important as we move forward with developing new therapies for these patients.”
The study reported on eight total individuals among three families with inherited, protein-truncating variants in the SYNGAP1 gene. In two of the families, the patient inherited the variant from a heterozygous parent who had symptoms of SYNGAP1-related disorders themselves. In the third family, the variant was inherited from a mosaic parent, meaning that the parent had only a small percentage of cells affected by the variant and did not have any symptoms.
The study also reported on two families with missense variants of uncertain significance, meaning that the variant causes an amino acid substitution, rather than shortening the protein, which can affect how the resulting protein functions. However, more work is needed to determine the clinical significance of these variants.
Study participants were identified through the SYNGAP1 ProMMiS natural history study, conducted by the Center for Epilepsy and Neurodevelopmental Disorders (ENDD) at CHOP and Penn Medicine. This ongoing work is aimed at recruiting as many individuals with SYNGAP1-related disorders as possible to track the progression of symptoms in this condition over time and set the stage for eventual clinical trials.
“In conducting this study, we are meeting a large number of families with SYNGAP1, and as a result, we are making additional discoveries like this one that we did not expect,” said senior study author Jillian McKee, MD, PhD, an ENGIN epileptologist who specializes in neurogenetic disorders at CHOP. “The familial variants we identified may be rare, but these ‘edge cases’ can provide valuable insight into the spectrum of symptoms and their genetic causes.”
This study was supported by the Center for Epilepsy and Neurodevelopmental Disorders (ENDD), the National Institute for Neurological Disorders and Stroke grants R01 NS127830-01A1, R01 NS131512-01 and K02 NS112600, the American Epilepsy Society, Pediatric Epilepsy Research Foundations and the SynGAP Research Fund through a Research Training Fellowship for Clinicians, and the American Academy of Neurology, the Epilepsy Foundation and the American Brain Foundation through the Susan Spencer Award.
Harrison et al, “Familial SYNGAP1 variants define the boundaries of a complex neurodevelopmental disorder with epilepsy.” Epilepsia. Online May 23, 2025. DOI: 10.1111/epi.18469.
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