Royal College of Surgeons in Ireland
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De-novo mutations in patients with chronic ultra-refractory epilepsy with onset after age five years

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journal contribution
posted on 2021-04-23, 17:01 authored by Mark McCormack, Ronan N McGinty, Xiaolin Zhu, Lisa Slattery, Erin L. Heinzen, EPIGEN Consortium, Daniel J Costello, Norman DelantyNorman Delanty, Gianpiero CavalleriGianpiero Cavalleri
We set out to investigate whether a de-novo paradigm could explain genetic causes of chronic ultra-refractory epilepsy, with onset later than the typical age for the epileptic encephalopathies. We performed exome sequencing on nine adult patients with MRI-negative epilepsy and no preceding intellectual disability. All had an onset of seizures after five years old and had chronic ultra-refractory epilepsy defined here as having failed more than six anti-epileptic drugs and currently experiencing ≥4 disabling seizures per month. Parents were sequenced to identify de-novo mutations and these were assessed for likelihood of pathogenicity based on the American College of Medical Genetics and Genomics (ACMG) criteria. We confirmed the presence of functional and predicted-damaging de-novo mutations in 3/9 patients. One of these pathogenic de-novo mutations, in DNM1L, was previously reported in a patient with severe epilepsy and chronic pharmacoresistance adding to the evidence for DNM1L as an epilepsy gene. Exome sequencing is a successful strategy for identifying de-novo mutations in paediatric epileptic encephalopathies and rare neurological disorders. Our study demonstrates the potential benefit of considering ultra-refractory epilepsy patients with later onset for genetic testing. Identifying genetic mutations underpinning severe epilepsy of unknown aetiology may provide new insight into the underlying biology and offers the potential for therapeutic intervention in the form of precision medicine in older patients.


Marie Curie Individual Fellowship (number 751761)

Science Foundation Ireland (SFI) under Grant Numbers 13/CDA/2223 and 16/RC/3948

European Regional Development Fund

FutureNeuro industry partners



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Published Citation

McCormack M, McGinty RN, Zhu X, Slattery L, Heinzen EL, EPIGEN Consortium, Costello DJ, Delanty N, Cavalleri GL. De-novo mutations in patients with chronic ultra-refractory epilepsy with onset after age five years. European Journal of Medical Genetics. 2020;63(1):103625

Publication Date

31 January 2019

PubMed ID



  • Beaumont Hospital
  • FutureNeuro Centre
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Neurological and Psychiatric Disorders


Elsevier BV


  • Published Version (Version of Record)