Genome-Wide Association Study of Epilepsy in a Japanese Population Identified an Associated Region at Chromosome 12q24

Abstract, originally published in Epilepsia

Objective: Although a number of genes responsible for epilepsy have been identified through Mendelian genetic approaches, and genome-wide association studies (GWASs) have implicated several susceptibility loci, the role of ethnic-specific markers remains to be fully explored. We aimed to identify novel genetic associations with epilepsy in a Japanese population.

Methods: We conducted a GWAS on 1825 patients with a variety of epilepsies and 7975 control individuals. Expression quantitative trait locus (eQTL) analysis of epilepsy-associated single nucleotide polymorphisms (SNPs) was performed using Japanese eQTL data.

Results: We identified a novel region, which is ~2 Mb (lead SNP rs149212747, p = 8.57 × 10-10 ), at chromosome 12q24 as a risk for epilepsy. Most of these loci were polymorphic in East Asian populations including Japanese, but monomorphic in the European population. This region harbors 24 transcripts including genes expressed in the brain such as CUX2, ATXN2, BRAP, ALDH2, ERP29, TRAFD1, HECTD4, RPL6, PTPN11, and RPH3A. The eQTL analysis revealed that the associated SNPs are also correlated to differential expression of genes at 12q24.

Significance: These findings suggest that a gene or genes in the CUX2-RPH3A ~2-Mb region contribute to the pathology of epilepsy in the Japanese population.

Reproductive Decision-Making in Families Containing Multiple Individuals With Epilepsy

Abstract, originally published in Epilepsia

Objective: This study evaluated factors influencing reproductive decision-making in families containing multiple individuals with epilepsy.

Methods: One hundred forty-nine adults with epilepsy and 149 adult biological relatives without epilepsy from families containing multiple affected individuals completed a self-administered questionnaire. Participants answered questions regarding their belief in a genetic cause of epilepsy (genetic attribution) and estimated risk of epilepsy in offspring of an affected person. Participants rated factors for their influence on their reproductive plans, with responses ranging from “much more likely” to “much less likely” to want to have a child. Those with epilepsy were asked, “Do you think you would have wanted more (or any) children if you had not had epilepsy?”

Results: Participants with epilepsy had fewer offspring than their unaffected relatives (mean = 1.2 vs. 1.9, p = .002), and this difference persisted among persons who had been married. Estimates of risk of epilepsy in offspring of an affected parent were higher among participants with epilepsy than among relatives without epilepsy (mean = 27.2 vs. 19.6, p = .002). Nineteen percent of participants with epilepsy responded that they would have wanted more children if they had not had epilepsy. Twenty-five percent of participants with epilepsy responded that “the chance of having a child with epilepsy” or “having epilepsy in your family” made them less likely to want to have a child. Having these genetic concerns was significantly associated with greater genetic attribution and estimated risk of epilepsy in offspring of an affected parent.

Significance: People with epilepsy have fewer children than their biological relatives without epilepsy. Beliefs about genetic causes of epilepsy contribute to concerns and decisions to limit childbearing. These beliefs should be addressed in genetic counseling to ensure that true risks to offspring and reproductive options are well understood.

Adult Phenotype of KCNQ2 Encephalopathy

Abstract, originally published in Neurogenetics

Background: Pathogenic KCNQ2 variants are a frequent cause of developmental and epileptic encephalopathy.

Methods: We recruited 13 adults (between 18 years and 45 years of age) with KCNQ2 encephalopathy and reviewed their clinical, EEG, neuroimaging and treatment history.

Results: While most patients had daily seizures at seizure onset, seizure frequency declined or remitted during childhood and adulthood. The most common seizure type was tonic seizures (early) infancy, and tonic-clonic and focal impaired awareness seizures later in life. Ten individuals (77%) were seizure-free at last follow-up. In 38% of the individuals, earlier periods of seizure freedom lasting a minimum of 2 years followed by seizure recurrence had occurred. Of the 10 seizure-free patients, 4 were receiving a single antiseizure medication (ASM, carbamazepine, lamotrigine or levetiracetam), and 2 had stopped taking ASM. Intellectual disability (ID) ranged from mild to profound, with the majority (54%) of individuals in the severe category. At last contact, six individuals (46%) remained unable to walk independently, six (46%) had limb spasticity and four (31%) tetraparesis/tetraplegia. Six (46%) remained non-verbal, 10 (77%) had autistic features/autism, 4 (31%) exhibited aggressive behavior and 4 (31%) destructive behavior with self-injury. Four patients had visual problems, thought to be related to prematurity in one. Sleep problems were seen in six (46%) individuals.

Conclusion: Seizure frequency declines over the years and most patients are seizure-free in adulthood. Longer seizure-free periods followed by seizure recurrence are common during childhood and adolescence. Most adult patients have severe ID. Motor, language and behavioral problems are an issue of continuous concern.

Mutations in the Neurochondrin Gene Linked to Epilepsy

Summary, originally published by Uppsala University

Mutations in the neurochondrin (NCDN) gene can cause epilepsy, neurodevelopmental delay and intellectual disability. The gene mutation significantly impairs contacts and signaling between neurons in the brain. This is the conclusion of a study led from Uppsala University and published in the American Journal of Human Genetics.

“The mutation may provide an additional explanation as to why people suffer from these conditions, making it easier to diagnose affected individuals. These are common ailments that are often diagnosed in preschool-age children. They raise concerns and questions among the parents of the affected children: Is this due to something going wrong during pregnancy, childbirth or infancy? Was there something wrong with our germ cells and is it hereditary? The mutations we have identified sometimes arise in individual germ cells prior to conception itself. It is then a matter of chance that they happen upon the neurochondrin gene to produce these effects,” says Niklas Dahl, senior consultant and professor of clinical genetics at Uppsala University’s Department of Immunology, Genetics and Pathology.

The study, which was led from Uppsala University, began by analyzing a worldwide database of genetic analyses of entire genomes. Researchers and physicians from around the world report genome abnormalities that they come across in patients or while conducting research, making it possible to see if any similar cases have been reported anywhere in the world. In Uppsala, researchers initially identified three cases of mutation in the NCDN gene.

Researchers Provide Complete Clinical Landscape for Gene Linked to Epilepsy and Autism

Summary, originally published by Children’s Hospital of Philadelphia

Researchers from Children’s Hospital of Philadelphia (CHOP) affiliated with the CHOP Epilepsy Neurogenetics Initiative (ENGIN) have compiled a complete genetic and clinical analysis of more than 400 individuals with SCN2A-related disorder, which has been linked to a variety of neurodevelopmental disorders, including epilepsy and autism. By linking clinical features to genetic abnormalities in a standardized format, the researchers hope their findings lead to improved identification and clinical intervention.

The study was published online by the journal Genetics in Medicine.

Pathogenic variants in the SCN2A gene can lead to a wide range of clinical features – or phenotypes – associated with neurodevelopmental disorders. Several studies have described the genetic information collected on individuals with disease-causing changes in this gene. However, while genetic information is collected in a standardized manner, data on phenotypes is not standardized, and prior to this study, the available data on clinical features of these patients had not been thoroughly analyzed, meaning that many correlations between the genotypes and phenotypes of these patients were often anecdotal.

UVA Scientist Developing Gene Therapy to Help Girls With Rett Syndrome

A University of Virginia School of Medicine scientist is developing an innovative gene therapy she hopes will slow disease progression and improve movement, coordination and communication in children with Rett syndrome. The approach also may be useful for battling other genetic disorders involving the X chromosome.

UVA researcher Sanchita Bhatnagar discovered that tiny bits of RNA, called microRNAs, play an important role in Rett, a rare genetic disorder that can impair children’s ability to speak, move and even breathe. Based on that finding, she is seeking to sop up those RNA bits, called microRNA, using absorbent particles called microRNA sponges.

Early work in lab models has produced promising results, and she hopes the approach could lead to a better quality of life for children with Rett.

“We are seeing that lab animals treated with this gene therapy are more mobile. They’re moving faster, they’re smarter,” Bhatnagar said. And if that translates into even modest improvements for children, it could make a big difference, she said: “If we can help a child to move more independently, or improve their ability to communicate, I think for a parent, that’s a big win.”

World-Leading Children’s Hospitals Partner to Find New Treatments for Pediatric Diseases

Summary, originally published by University College London

Four leading children’s research institutions on three continents are joining forces to decipher pediatric illnesses, including rare diseases, and find better treatments.

The four pediatric hospitals — Boston Children’s Hospital; UCL Great Ormond Street Institute for Child Health and Great Ormond Street Hospital (London); the Murdoch Children’s Research Institute with The Royal Children’s Hospital (Melbourne); and The Hospital for Sick Children (SickKids) in Toronto — are working together to evaluate genomic data, clinical data from patients, and scientific and medical expertise to accelerate discovery and therapeutic development.

The partnership, known as the International Precision Child Health Partnership (IPCHiP), is the first major global collaboration around genomics and child health. The founding partners anticipate that additional institutions will join the collaboration in the future.

IPCHiP’s first project will involve epilepsy in infants, bringing together efforts already underway at the four hospitals.

Investigators at each site will enroll babies under age one with epilepsy, sequence their genomes, change treatment based on the findings when appropriate, and follow the children’s development long term. No patient will be identifiable from the data used, and no patient data will be shared across international borders.

Study Shows Genetic Testing Program Lowered Age of Molecular Diagnosis in Children

Summary, originally published in Dravet Syndrome News

By implementing a free-of-charge epilepsy genetic testing program, it is possible to lower the average age of molecular diagnosis of children with epileptic disorders caused by mutations in the SCN1A gene, such as Dravet syndrome, from more than 6 to less than 2 years of age.

The study with that finding, “Reducing the Time to Diagnosis and Increasing the Detection of Individuals With SCN1A-Related Disease Through a No Cost, Sponsored Epilepsy Genetic Testing Program,” was presented during the American Epilepsy Society (AES) 2020 Virtual Annual Meeting.

Genetic mutations in the SCN1A gene have been associated with a wide spectrum of epileptic disorders, including Dravet syndrome, generalized epilepsy with febrile seizures plus (GEFS+), and early infantile epileptic encephalopathy (EIEE).

According to a previous study, from 2011 to 2015, the average age of molecular diagnosis of patients with forms of epilepsy associated with SCN1A mutations was 6.2 years.

“As precision medicine therapies emerge, it is becoming increasingly important to diagnose SCN1A-related disorders before disease progression,” the researchers wrote.

Research Grant of Over 2 Million Euros ($2.5 Million) Offers New Hope for Children with Rare Epilepsy

Summary, originally published by Schinzel-Giedion Syndrome Foundation

Funding from two major European grants has been awarded to an international group of researchers to find treatments for the devastating rare genetic disease Schinzel-Giedion Syndrome (SGS).

The grants are the first major funding awarded for SGS research.

Nuala Summerfield, Founder and Chair of UK based patient group The Schinzel-Giedion Syndrome Foundation said: “My daughter Ophelia has Schinzel-Giedion Syndrome and has battled her entire short life with multiple daily seizures and many other severe health and developmental problems. There are no effective treatments currently available for SGS, so it is wonderful news that SGS is now receiving such commitment from the scientific community. Our patient advocacy group and our international SGS community will now have the unique opportunity to collaborate closely with these world class scientists to help them to develop new treatments for rare epilepsies.”

The funding comes from the European Joint Program on Rare Diseases (EJP RD), co-funded by the European Commission. The TREAT-SGS project was selected from 173 eligible proposals and will receive 1.6 million Euros. The focus of the TREAT-SGS project is the development and preclinical testing in human cell models and transgenic mice of novel treatments for Schinzel-Giedion Syndrome. The project is a collaboration between the UK based patient group The Schinzel-Giedion Syndrome Foundation and academic researchers in Canada, Italy, Sweden and Germany, facilitated by Dr. Carl Ernst.

Screening of Genetically Diverse Mice Identifies Novel Rodent Models of Diverse Epilepsy Outcomes

Funded by the generosity of families who have experienced a loss due to SUDEP.

Key Points:

CURE Epilepsy Taking Flight Award grantee Dr. Bin Gu and colleagues used genetically diverse mouse strains to identify those that vary in seizure susceptibility, seizure spread, seizure development, and sudden unexpected death in epilepsy (SUDEP).
Initial screening of these mice identified four different genetic strains that suddenly and unpredictably died after inducing a single seizure, suggesting these mice may represent novel models for studying SUDEP.
Further genetic characterization of these four mouse strains should provide valuable insights into the underlying genetic risk factors for SUDEP.

Deep Dive:

Dr. Bin Gu, PhD

SUDEP is the sudden, unexpected death of someone with epilepsy who otherwise appears healthy. To facilitate an understanding of the complex genetic basis of SUDEP, studies need to use genetically diverse mouse populations [1,2], such as the “Collaborative Cross” [3,4], which can help identify different genetic risk factors that control SUDEP susceptibility.

With the help of a CURE Epilepsy Taking Flight Award, Dr. Bin Gu and his colleagues in the laboratories of Drs. Ben Philpot and Fernando Pardo-Manuel de Villena at the University of North Carolina at Chapel Hill used Collaborative Cross mice to identify mouse strains that were more likely to have seizures, were more prone to having subsequent seizures, were more susceptible to having their seizures spread throughout the brain and were especially vulnerable to SUDEP [5].

The researchers screened mice from this population to identify candidate genes and genetic variants linked to many key symptoms of epilepsy. For example, within this population of mice, when Dr. Gu induced epilepsy, he observed that some mouse strains were resistant to developing epilepsy, whereas others were more susceptible. Identifying the genetics of the resistant strains is important for understanding the mechanisms underlying seizures and developing new ways of stopping seizures before full-blown epilepsy develops.

Among the groups of mice that Dr. Gu studied, four strains of mice died suddenly after a single seizure that was not fatal in “normal” mice. Although the precise cause of sudden death in these mice is currently unknown, the specific strains may eventually provide important clues to the causes of SUDEP in humans.

Dr. Gu’s upcoming research will focus on characterizing these “pro-SUDEP” strains, identifying those genes that control SUDEP susceptibility and resistance and studying the biological causes, including cardiac and respiratory events, that can provoke SUDEP. Such an understanding will hopefully lead to effective strategies to prevent SUDEP.

By providing Dr. Gu with critical initial funding for his research through a Taking Flight Award, CURE Epilepsy has also helped advance Dr. Gu’s career. He will soon establish his own independent lab as an Assistant Professor of Neuroscience at Ohio State University, where he will continue to pursue his passion for epilepsy research.

Dr. Bin Gu is a postdoctoral fellow at the University of North Carolina at Chapel Hill.

Literature Cited
[1] Saul, M.C. et al. High-diversity mouse populations for complex traits. Trends Genet. 2019; 35(7): 501-514.
[2] Bogue, M.A. et al Collaborative cross and diversity outbred data resources in the mouse phenome database. Mamm. Genome 2015; 26(9-10): 511-520.
[3] Churchill, G.A. et al. Complex Trait Consortium. The collaborative cross, a community resource for the genetic analysis of complex traits. Nature Genetics 2004; 36(11): 1133-1137.
[4] Srivastava, A. et al. Genomes of the mouse collaborative cross. Genetics 2017; 206(2): 537-556.
[5] Gu, B. et al. Collaborative cross mice reveal extreme epilepsy phenotypes and genetic loci for seizure susceptibility. Epilepsia 2020; 61(9): 2010-2021.

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