Phenotypic concordance in 70 families with IGE-implications for genetic studies of epilepsy

A crucial issue in the genetic analysis of idiopathic generalized epilepsy (IGE) is deciding on the phenotypes that are likely to give the greatest power to detect predisposing variants. A complex inheritance pattern and unclear nature of the genotype-phenotype correlation makes this task difficult. In the absence of much definitive genetic information to clarify this correlation, we inferred the putative effects of predisposing genes by studying the clustering of various phenotypic features, both clinical and electrophysiological, within families.

We examined the distribution of clinical features among relatives of a proband in 70 French-Canadian families with a minimum of two affected individuals with a clear diagnosis of IGE and then, using concordance analysis, identified the relative genetic influences on IGE syndrome, seizure type, age-at-onset, and EEG features.

The mean number of affected individuals with IGE per family was three. One-third of relatives had the same syndrome as the proband. 16-22.5% of relatives of a proband with one of the absence syndromes had juvenile myoclonic epilepsy (JME). Conversely, 27% of relatives of probands with JME had an absence syndrome. 15% of relatives displayed the exact constellation of seizure types as the proband. Concordance analysis demonstrated greater clustering within families of IGE syndrome, seizure type, and age-at-onset than would be expected by chance. Significant concordance was not evident for EEG features.

There was a large degree of clinical heterogeneity present within families. However we found evidence for clustering of a number of clinical features. Further refinement of the phenotypes used in genetic studies of complex IGE is necessary for progress to be made.