Comorbid epilepsy linked to gene repeats


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Pathogenic autosomal copy number variations were found in about 11% of epilepsy patients with comorbidities and 12.7% when possibly pathogenic variations were included, in a genetic study of over 1,000 patients in eight European epilepsy centers.

Subjects with nonneurological comorbidities, particularly dysmorphism, were more than four times as likely to carry a pathogenic copy number variation (CNV), a repeat in the genetic code. When seizures are associated with dysmorphism, intellectual disability (ID), and other comorbidities, “there is a higher probability of identifying a pathogenic CNV than in epilepsy alone,” said investigators led by Antonietta Coppola, PhD, a clinical research associate at the University of Naples Federico II Epilepsy Centre, in Italy.

“Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection,” they said.

She and her team are among many researchers unraveling the role of genetics in epilepsy. It’s estimated that up to 70% of cases have a genetic component, especially when diagnosed in childhood. Studies are proving that genetic anomalies – including CNVs – lead to specific and particularly devastating epileptic phenotypes (Epilepsia. 2019 Mar 13. doi: 10.1111/epi.14683).

The main driver of genetic testing for now seems to be diagnostic, to get a better idea of exactly what’s going on in particularly tough cases, but there might also be treatment implications. Whatever the case, it’s becoming important to test “for CNVs in patients with epilepsy and associated comorbidities,” the investigators said.

They pulled together CNV data from 1,097 patients with epilepsy and comorbid features including, among others, ID; autism; dysmorphic features; structural brain abnormalities; multidrug resistance; and psychiatric symptoms.

Overall, 120 (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 (1.7%) carried at least one autosomal CNV classified as possibly pathogenic.

credit: Chrisglez18/Wikimedia Commons/CC BY-SA 4.0

credit: Domaina/Wikimedia Commons/CC BY-SA 3.0

They also found several CNVs that included the genes HNRNPU (1q44) and RORB (9p21.13), both recently associated with epilepsy. “In our cohort, five patients carried CNVs mapping to the 1q43q44 critical region, and in addition to the HNRNPU gene, in two duplications and one deletion.”

The chromosomal “rearrangement included also the AKT3 gene, which might contribute to brain abnormalities observed in these patients. Patients with deletions showed dysmorphic features, early onset psychomotor delay, and early onset epilepsy,” they said.

Three patients carried deletions involving the RORB gene, and exhibited ID and generalized epilepsy, including absence seizures with eyelid myoclonia, and autistic features in one patient, “supporting a role for RORB in GGE [genetic generalized epilepsy] and, more broadly, in several neurodevelopmental disorders,” the team said.

They also found a de novo 18q12.3 deletion in a new gene candidate for comorbid epilepsy, SETBP1, linked to severe ID, specific craniofacial features, and seizures.

It’s unknown where the work will lead, but the investigators wanted their readers to know that they had come up with a way to pull CNV findings together from centers using different genetic platforms. Doing so is the only way to unravel the genetic mystery, so they shared their method.

They classified CNVs known to be present in healthy people as benign. Remaining CNVs were classified as pathogenic if they met certain criteria, including at least an 80% overlap with a CNV known to be associated with epilepsy. CNVs were tagged as “possibly pathogenic” if they involved a gene associated with epilepsy, but the patient didn’t fit the phenotype reported in the literature, among other qualifiers.

The work was funded by the Wellcome Trust, the University of Antwerp, and others. Dr. Coppola is an adviser and speaker for Eisai. Other investigators reported ties to Eisai and numerous other companies, including Novartis and Takeda.

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