Medical sequencing of candidate genes for nonsyndromic cleft lip and palate - PubMed (original) (raw)

doi: 10.1371/journal.pgen.0010064. Epub 2005 Dec 2.

Joseph R Avila, Sandra Daack-Hirsch, Ecaterina Dragan, Têmis M Félix, Fedik Rahimov, Jill Harrington, Rebecca R Schultz, Yoriko Watanabe, Marla Johnson, Jennifer Fang, Sarah E O'Brien, Iêda M Orioli, Eduardo E Castilla, David R Fitzpatrick, Rulang Jiang, Mary L Marazita, Jeffrey C Murray

Affiliations

Medical sequencing of candidate genes for nonsyndromic cleft lip and palate

Alexandre R Vieira et al. PLoS Genet. 2005 Dec.

Abstract

Nonsyndromic or isolated cleft lip with or without cleft palate (CL/P) occurs in wide geographic distribution with an average birth prevalence of 1/700. We used direct sequencing as an approach to study candidate genes for CL/P. We report here the results of sequencing on 20 candidate genes for clefts in 184 cases with CL/P selected with an emphasis on severity and positive family history. Genes were selected based on expression patterns, animal models, and/or role in known human clefting syndromes. For seven genes with identified coding mutations that are potentially etiologic, we performed linkage disequilibrium studies as well in 501 family triads (affected child/mother/father). The recently reported MSX1 P147Q mutation was also studied in an additional 1,098 cleft cases. Selected missense mutations were screened in 1,064 controls from unrelated individuals on the Centre d'Etude du Polymorphisme Humain (CEPH) diversity cell line panel. Our aggregate data suggest that point mutations in these candidate genes are likely to contribute to 6% of isolated clefts, particularly those with more severe phenotypes (bilateral cleft of the lip with cleft palate). Additional cases, possibly due to microdeletions or isodisomy, were also detected and may contribute to clefts as well. Sequence analysis alone suggests that point mutations in FOXE1, GLI2, JAG2, LHX8, MSX1, MSX2, SATB2, SKI, SPRY2, and TBX10 may be rare causes of isolated cleft lip with or without cleft palate, and the linkage disequilibrium data support a larger, as yet unspecified, role for variants in or near MSX2, JAG2, and SKI. This study also illustrates the need to test large numbers of controls to distinguish rare polymorphic variants and prioritize functional studies for rare point mutations.

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Conflict of interest statement

Competing interests. The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Protein Comparisons of the Available Gene Orthologs for GLI2 S1213Y and SPRY2 D20A

GLI2 S1213Y (A) and SPRY2 D20A (B): Green bars indicate degree of conservation in each site. Amino acids in red indicate the mutation sites. All mutation comparisons are available as supplemental material at

http://genetics.uiowa.edu/publications.html

.

Figure 2

Figure 2. Family Pedigree of the Filipino Family Segregating the MSX1 P147Q Mutation

PP (proline–proline) indicates the wild-type genotype. PQ (proline–glutamine) indicates the genotype of the individuals carrying the mutation.

Figure 3

Figure 3. Family Pedigree of the Filipino Proband with the LHX8 E221A Mutation

The segregation pattern of the mutation is not consistent with a simple Mendelian model for the disease. EE (glutamic acid–glutamic acid) indicates the wild-type genotype. EA (glutamic acid–alanine) indicates the genotype of the individuals carrying the mutation.

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