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Genetic evidence for the role of loci at 19q13 in cleft lip and palate
  1. A Warrington1,
  2. A R Vieira1,*,
  3. K Christensen2,
  4. I M Orioli3,
  5. E E Castilla4,
  6. P A Romitti5,
  7. J C Murray1,*
  1. 1Department of Pediatrics, University of Iowa, Iowa City, IA, USA
  2. 2Centre for the Prevention of Congenital Malformations, University of Southern Denmark, DK-5000 Odense C, Denmark
  3. 3Latin American Collaborative Study of Congenital Malformations (ECLAMC), Department of Genetics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
  4. 4Latin American Collaborative Study of Congenital Malformations (ECLAMC), Department of Genetics, Oswaldo Cruz Institute, Rio de Janeiro, RJ, Brazil
  5. 5Department of Epidemiology, University of Iowa, Iowa City, IA, USA
  1. Correspondence to:
 Jeffrey C Murray
 Department of Pediatrics, University of Iowa, 2182 ML, Iowa City, IA 52242, USA; jeff-murray{at}


Background: Clefts of the lip and palate are common birth defects, affecting approximately 1 in 700 births worldwide. The aetiology of clefting is complex, with multiple genetic and environmental influences.

Methods: Genotype based linkage disequilibrium analysis was conducted using the family based association test (FBAT) and the likelihood ratio test (LRT). We also carried out direct sequencing of the PVR and PVRL2 candidate genes based on their homology to PVRL1, a gene shown previously to cause Margarita Island clefting. Participants included 434 patients with cleft lip with or without cleft palate or cleft palate only and their mothers from eight countries in South America, 205 nuclear triads (father-mother-affected child) from Iowa, 541 nuclear triads from Denmark, and 100 patients with cleft lip and palate from the Philippines.

Results: An allelic variant in the PVR gene showed statistically significant association with both South American and Iowa populations (p = 0.0007 and p = 0.0009, respectively). Direct sequencing of PVR and PVRL2 yielded 26 variants, including two rare amino acid changes, one in each gene, which were not seen in controls.

Conclusions: We found an association between a common variant in a gene at 19q and isolated clefting in two heterogeneous populations. However, it is unclear from our data if rare variants in PVR and PVRL2 are sufficient to cause clefting in isolation.

  • CEPH, Centre D’Etude du Polymorphisme Humain
  • CL/P, cleft lip with or without cleft palate
  • CPO, cleft palate only
  • ECLAMC, Latin American Collaborative Study of Congenital Malformations
  • ESEs, exonic splicing enhancers
  • FBAT, family based association test
  • LRT, likelihood ratio test
  • PVR, poliovirus receptor
  • SNP, single nucleotide polymorphism
  • TDT, transmission disequilibrium tests
  • cleft lip and palate
  • cleft palate
  • PVR
  • PVRL2
  • 19q13

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  • * These authors equally contributed to the organisation and development of this work

  • This work is supported by NIH Grants DE 08559, 5 D43 TW05503, and P50 DE016215 (JCM); R01 DE 11948 and the Egmont Foundation (KC); and The March of Dimes Foundation Grant FY02-212; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazil 522059/96-1; Agencia Nacional de Promocion Cientifica y Technologica, Consejo Nacional de Investigaciones Cientificas y Technologicas, Argentina; and Grant PICT 495 (EEC)

  • Competing interests: none declared