a1 Department of Pediatrics, University of Iowa, United States of America (*currently at Department of Pathology and Lab Medicine, University of North Carolina, United States of America).
a2 Department of Human Genetics, Nagasaki University Graduate School of Biomedical sciences, Nagasaki, Japan.
a3 Biostatistics Branch, National Institute of Environmental Health Sciences (NIEHS), United States of America.
a4 Craniofacial Development, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia.
a5 Servico de Aconselhamento, Genetico da Universidade Estadual Paulista, Botucatu, Brazil.
a6 Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Denmark.
a7 Department of Pediatrics, University of Iowa, United States of America. email@example.com
Phenotypically discordant monozygotic twins offer the possibility of gene discovery through delineation of molecular abnormalities in one member of the twin pair. One proposed mechanism of discordance is postzygotically occurring genomic alterations resulting from mitotic recombination and other somatic changes. Detection of altered genomic fragments can reveal candidate gene loci that can be verified through additional analyses. We investigated this hypothesis using array comparative genomic hybridization; the 50K and 250K Affymetrix GeneChip® SNP arrays and an Illumina custom array consisting of 1,536 SNPs, to scan for genomic alterations in a sample of monozygotic twin pairs with discordant cleft lip and/or palate phenotypes. Paired analysis for deletions, amplifications and loss of heterozygosity, along with sequence verification of SNPs with discordant genotype calls did not reveal any genomic discordance between twin pairs in lymphocyte DNA samples. Our results demonstrate that postzygotic genomic alterations are not a common cause of monozygotic twin discordance for isolated cleft lip and/or palate. However, rare or balanced genomic alterations, tissue-specific events and small aberrations beyond the detection level of our experimental approach cannot be ruled out. The stability of genomes we observed in our study samples also suggests that detection of discordant events in other monozygotic twin pairs would be remarkable and of potential disease significance.
(Received November 11 2008)
(Accepted June 17 2009)
c1 Address for correspondence: Jeffrey C. Murray, MD, University of Iowa, Department of Pediatrics, S. Grand Avenue, 2182 ML, Iowa City IA 52242 USA.