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Discordant MZ Twins With Cleft Lip and Palate: A Model for Identifying Genes in Complex Traits

Published online by Cambridge University Press:  21 February 2012

Maria Adela Mansilla ,
Jane Kimani ,
Laura E. Mitchell ,
Kaare Christensen ,
Dorret I. Boomsma ,
Sandy Daack-Hirsch ,
Buena Nepomucena ,
Diego F. Wyszynski ,
Temis M. Felix  and
Nicholas G. Martin
...Show all authors
Maria Adela Mansilla
Affiliation:
University of Iowa, Department of Pediatrics, Iowa City, Iowa, United States of America.
Jane Kimani
Affiliation:
University of Iowa, Department of Pediatrics, Iowa City, Iowa, United States of America.
Laura E. Mitchell
Affiliation:
The Texas A & M University System, Health Science Center, Institute of Biosciences and Technology, Houston, Texas, United States of America.
Kaare Christensen
Affiliation:
Institute of Public Health, University of Southern Denmark: Main Campus, Odense University, Odense, Denmark.
Dorret I. Boomsma
Affiliation:
Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.
Sandy Daack-Hirsch
Affiliation:
University of Iowa, Department of Pediatrics, Iowa City, Iowa, United States of America.
Buena Nepomucena
Affiliation:
Hope Foundation, Bacolod City, Philippines.
Diego F. Wyszynski
Affiliation:
Boston University School of Medicine, Genetics Program, Boston, Massachusetts, United States of America.
Temis M. Felix
Affiliation:
Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil.
Nicholas G. Martin
Affiliation:
Genetic Epidemiology Unit, Queensland Institute of Medical Research, Brisbane, Australia.
Jeffrey C. Murray*
Affiliation:
University of Iowa, Department of Pediatrics, Iowa City, Iowa, United States of America; Institute of Public Health, University of Southern Denmark: Main Campus, Odense University, Odense, Denmark. jeff-murray@uiowa.edu
*
*Address for correspondence: Jeffrey C. Murray, University of Iowa, Department of Pediatrics, 2182 ML, S Grand Avenue, Iowa City, Iowa 52242, USA.

Abstract

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Monozygotic (MZ) twins may be discordant for complex traits due to differential environmental exposure in utero, epigenetic variability in imprinting, X chromosome inactivation, or stochastic effects. Occasionally MZ twins may be discordant for chromosomal and single gene disorders due to somatic mosaicism. For complex traits, which are due to the interactive effects of multiple genes and environmental factors, the affected twin of a discordant MZ pair offers the possibility for identifying somatic mutations in candidate genes. DNA sequencing of candidate genes in discordant MZ twins can identify those rare etiologic mutational events responsible for the different phenotypes since the confounding effects of common single nucleotide polymorphisms are eliminated, as DNA sequences should be identical in MZ pairs. In this report we describe the extensive DNA sequencing of 18 candidate genes in a sample of MZ and dizygotic (DZ) twins with nonsyndromic cleft lip with or without cleft palate. We were unable to identify any somatic differences in approximately 34 Kb of DNA sequenced in 13 MZ pairs, for a total of approximately 900 Kb of sequence comparisons, supporting the hypothesis that nonetiologic posttwinning mutations are rare. While no etiologic variants were identified in this study, sequence comparisons of discordant MZ twins can serve as a tool for identifying etiologic mutations in clefting and other complex traits.

Type
Articles
Information
Twin Research and Human Genetics , Volume 8 , Issue 1 , 01 February 2005 , pp. 39 - 46
Copyright
Copyright © Cambridge University Press 2005