NEW YORK – A founder event that took place roughly 800 years ago in Britain gave rise to a risk allele for autosomal dominant childhood epilepsy in the SCN1B gene, new research suggests. The allele was later introduced to Australia, the US, and other parts of the world via British migrants.
As reported in the American Journal of Human Genetics on Tuesday, researchers who discovered the event focused on an autosomal dominant familial epilepsy syndrome known as “genetic epilepsy with febrile seizures plus” (GEFS+), retracing the genetic history of an SCN1B gene variant that had previously been implicated in the condition.
“Within families, a spectrum of phenotypes beginning in infancy or childhood is seen, ranging from mild (febrile seizures) to severe (epilepsy with myoclonic-atonic seizures and Dravet syndrome) disorders,” corresponding author Samuel Berkovic, a researcher affiliated with the University of Melbourne’s Epilepsy Research Centre, and his colleagues explained.
Using genotyping profiles and related haplotype patterns for nearly four dozen individuals from 14 epilepsy-affected families in Australia, the UK, and the US — along with subsequent analyses on 74 exome-sequenced UK Biobank participants found to carry the same SCN1B change — the team saw signs that the variant stemmed from a founder mutation that first arose some 800 years ago.
“All individuals carried haplotypes matching the epilepsy-affected families, suggesting all instances of the variant derive from a single mutational event,” the authors wrote.
Though disease-related founder events are more often linked to autosomal recessive conditions diagnosed later in life, the team speculated that a combination of incomplete disease penetrance and a relatively mild epileptic phenotype may have helped to keep the risk allele circulating in the population despite its ties to an early-onset disease that is inherited in an autosomal dominant manner.
“These findings suggest variants present in the population at low frequencies should be considered potentially pathogenic in mild phenotypes with incomplete penetrance and may be more important than previously thought,” the authors suggested. “Such variants may be erroneously dismissed in cohort studies or by clinical laboratories because of their population frequency.”
Indeed, the investigators estimated that the SCN1B risk variant appears to be far more common in European individuals enrolled in the UK Biobank project than in the massive collection of exome and genome sequence data contained in the Genome Aggregation Database (gnomAD).
“The age of this common founder suggests the variant arose prior to White settlement of Australia in the late 1700s,” they reported, adding that “the additional finding that this variant is present in the European cohort of the UK Biobank at 14 times the frequency seen in gnomAD, together with the ancestral origins of the epilepsy families, supports a British origin of the variant, which subsequently spread through settlement of Australia and the USA following the migration of individuals from Britain.”