A study to find novel genetic abnormalities associated with epile.pdf (16.58 MB)
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A study to find novel genetic abnormalities associated with epilepsy in affected Irish families.

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posted on 22.11.2019, 18:27 authored by Gerard O'Connor

Background; Epilepsy is one of the commonest neurological illnesses. There is considerable evidence that, in many cases, epilepsy is partly or completely genetic in aetiology. However, in spite of progress in certain Mendelian epilepsy syndromes, the genetic cause of epilepsy within families often remains unclear. With the advent of techniques such as whole exome sequencing, it may now be possible to identify the novel genetic variations underlying epilepsy in affected families. The aim of this study is to use whole exome sequencing to identify novel genetic abnormalities associated with epilepsy in affected Irish families. These novel genetic abnormalities will act as candidate causal variants for further study.

Methods; We sought to identify Irish families with strong histories of epilepsy. Familes were considered for inclusion if the index case, one of their first degree relatives and one other individual in the family were affected by epilepsy. In each family identified, we clinically phenotyped individuals who were affected and unaffected by epilepsy syndromes. From each participant, we obtained a tissue sample (blood or saliva) for DNA analysis. In a number o f selected families, we performed genetic analysis using whole exome sequencing looking for novel genetic variations which could be the cause of epilepsy in these families.

Results; We identified 96 families who met the criteria for inclusion on initial assessment, of whom 11 were recruited, representing a total of 110 individuals. There was considerable variability of phenotypes within the families identified. Affected individuals from four families had whole exome sequencing, with one other family having candidate gene analysis based on the results of previous screening of a family member. We identified novel genetic variations which could be candidates for further study as a possible cause for the epilepsy syndromes seen in three of the five families analysed. In one family, we identified a novel variation in a known epilepsy gene (A348Y in the SLC2A1 gene). In two other families, novel mutations were identified in genes not previously demonstrated to be associated with epilepsy (CHRNB3 and NARG2)

Conclusion; Our study demonstrates that whole exome sequencing can be used to characterise novel genetic variations in Irish families with a strong history of epilepsy. Further studies are necessary to demonstrate that these abnormalities are causal for the epilepsy syndromes seen.


First Supervisor

Dr Norman Delanty

Second Supervisor

Dr Gianpiero Cavalleri


A thesis submitted for the degree of Doctor of Medicine from the Royal College of Surgeons in Ireland in 2014.

Published Citation

O'Connor G. A study to find novel genetic abnormalities associated with epilepsy in affected Irish families [MD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2014.

Degree Name

Doctor of Medicine (MD)

Date of award


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