Intractable epilepsy of infancy due to homozygous mutation in the EFHC1 gene.
OBJECTIVE
The molecular etiology of primary intractable epilepsy in infancy is largely unknown. We studied a nonconsanguineous Moroccan-Jewish family, where three of their seven children presented with intractable seizures and died at 18-36 months.


METHODS
Homozygous regions were searched using 250 K DNA single nucleotide polymorphism (SNP) array. The sequence of 50 Mb exome of a single patient was determined using SOLiD 5500XL deep sequencing analyzer.


RESULTS
A single homozygous 11.3 Mb genomic region on chromosome 6 was linked to the disease in this family. This region contained 110 genes encoding a total of 1,000 exons. Whole exome sequencing revealed a single pathogenic homozygous variant within the critical region. The mutation, Phe229Leu in the EFHC1 gene was previously shown, in a carrier state, to be associated with juvenile myoclonic epilepsy.


CONCLUSIONS
Although heterozygosity for the Phe229Leu mutation is known to be associated with a relatively benign form of epilepsy in adolescence; homozygosity for the same mutation is associated with lethal epilepsy of infancy. Given the considerable carrier rate of this mutation worldwide, the sequence of the EFHC1 gene should be determined in all patients with primary intractable epilepsy in infancy.
Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel. itberg@hadassah.org.il
Itai
I
Berger
Talya
T
Dor
Jonatan
J
Halvardson
Simon
S
Edvardson
Avraham
A
Shaag
Lars
L
Feuk
Orly
O
Elpeleg
D002135:Calcium-Binding Proteins / Q000235:genetics*; D002675:Child, Preschool; D004827:Epilepsy / Q000235:genetics*; D059472:Exome / Q000235:genetics; D017809:Fatal Outcome; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D002135:Calcium-Binding Proteins; C489648:EFHC1 protein, human