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

• Published in: The New England journal of medicine Vol. 363; no. 14; pp. 1335 - 1340
• Main Authors: Vadlamudi, Lata, Dibbens, Leanne M, Lawrence, Kate M, Iona, Xenia, McMahon, Jacinta M, Murrell, Wayne, Mackay-Sim, Alan, Scheffer, Ingrid E, Berkovic, Samuel F
• Format: Journal Article
• Language: English
• Published: Waltham, MA Massachusetts Medical Society 30.09.2010
• Subjects: Adult; Biological and medical sciences; Epilepsies, Myoclonic - genetics; Female; Frameshift Mutation; General aspects; Genetic Markers; Germ-Line Mutation; Humans; Infant; Medical sciences; Mutagenesis; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Nerve Tissue Proteins - genetics; Polymerase Chain Reaction; Sequence Analysis, DNA; Sodium Channels - genetics; Time Factors; Twins, Monozygotic - genetics; Medicine; Mutagenesis; Sodium; Temporal study; Genetics; Ionic channel; Mutation; Timing; De novo; Twin
• ISSN: 0028-4793; 1533-4406; 1533-4406
• DOI: 10.1056/NEJMoa0910752

This study of monozygous twins, in which one twin has Dravet's syndrome and the other does not, suggests that the mutation occurred in the early morula that gave rise to the affected twin. De novo mutations cause sporadic forms of a range of mendelian disorders, including tuberous sclerosis, neurofibromatosis, achondroplasia, 1 and Dravet's syndrome. Recently, de novo copy-number variations have been identified as a cause of sporadic cases of some mendelian disorders and perhaps more commonly as susceptibility alleles for complex disorders. Thus, de novo mutagenesis is an important mechanism in human disease and probably explains an appreciable fraction of sporadic and apparently nongenetic disorders. 1 Twins represent a unique resource for studying the timing of de novo mutagenesis. There are numerous case reports of genetic disorders in which monozygous twin pairs are phenotypically discordant. . . .