Timing of De Novo Mutagenesis — A Twin Study of Sodium-Channel Mutations — NEJM

Timing of De Novo Mutagenesis — A Twin Study of Sodium-Channel Mutations — NEJM

Timing of De Novo Mutagenesis — A Twin Study of Sodium-Channel Mutations

Lata Vadlamudi, M.B., B.S., Ph.D., Leanne M. Dibbens, Ph.D., Kate M. Lawrence, B.Sc., Xenia Iona, Dip.Biomed.Sci., Jacinta M. McMahon, B.Sc., Wayne Murrell, Ph.D., Alan Mackay-Sim, Ph.D., Ingrid E. Scheffer, M.B., B.S., Ph.D., and Samuel F. Berkovic, M.D.

N Engl J Med 2010; 363:1335-1340September 30, 2010

De novo mutations are a cause of sporadic disease, but little is known about the developmental timing of such mutations. We studied concordant and discordant monozygous twins with de novo mutations in the sodium channel α1 subunit gene (SCN1A) causing Dravet's syndrome, a severe epileptic encephalopathy. On the basis of our findings and the literature on mosaic cases, we conclude that de novo mutations in SCN1A may occur at any time, from the premorula stage of the embryo (causing disease in the subject) to adulthood (with mutations in the germ-line cells of parents causing disease in offspring).