Evidence for linkage of nonsyndromic cleft lip with or without cleft palate to a region on chromosome 2

Zeiger, Joanna S.; Hetmanski, Jacqueline B.; Beaty, Terri H.; Vanderkolk, Craig A.; Wyszynski, Diego F.; Bailey-Wilson, Joan E.; Luna, R; Perandones, Claudia; Tolarová, M; Mosby, Terezie T.; Bennun, Ricardo D.; Segovia, Mabel; Calda, Pavel; Pugh, Elizabeth; Doheny, Kim; McIntosh, Iain

doi:10.1038/sj.ejhg.5201052

Cited by 32 publications

(22 citation statements)

References 31 publications

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“…1, which also identiWes two key candidate genes (TGFA and SATB2). Regions of linkage reported by Prescott et al (2000), Marazita et al (2002), Zeiger et al (2003), as well as those from the meta-analysis of Marazita et al (2004) are also noted. Table 2 lists the 104 genes or gene clusters on chromosome 2 tested here, along with seven regions where individual SNPs were typed to provide additional coverage.…”

Section: Resultsmentioning

confidence: 89%

Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations

et al. 2006

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Isolated oral clefts, including cleft lip with/without cleft palate (CL/P) and cleft palate (CP), have a complex and heterogeneous etiology. Case-parent trios from three populations were used to study genes spanning chromosome 2, where single nucleotide polymorphic (SNP) markers were analyzed individually and as haplotypes. Case-parent trios from three populations (74 from Maryland, 64 from Singapore and 95 from Taiwan) were genotyped for 962 SNPs in 104 genes on chromosome 2, including two well-recognized candidate genes: TGFA and SATB2. Individual SNPs and haplotypes (in sliding windows of 2-5 SNPs) were used to test for linkage and disequilibrium separately in CL/P and CP trios. A novel candidate gene (ZNF533) showed consistent evidence of linkage and disequilibrium in all three populations for both CL/P and CP. SNPs in key regions of ZNF533 showed considerable variability in estimated genotypic odds ratios and their significance, suggesting allelic heterogeneity. Haplotype frequencies for regions of ZNF533 were estimated and used to partition genetic variance into among-and within-population components. Wright's fixation index, a measure of genetic diversity, showed little difference between Singapore and Taiwan compared with Maryland. The tensin-1 gene (TNS1) also showed evidence of linkage and disequilibrium among both CL/P and CP trios in all three populations, albeit at a lower level of significance. Additional genes (VAX2, GLI2, ZHFX1B on 2p; WNT6-WNT10A and COL4A3-COL4A4 on 2q) showed consistent evidence of linkage and disequilibrium only among CL/P trios in all three populations, and TGFA showed significant evidence in two of three populations.

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Section: Resultsmentioning

confidence: 89%

Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations

et al. 2006

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“…A recent development that deserves notice is the International HapMap project to identify patterns of association between markers within the human genome [92]. It is well recognized that association can occur in segments -termed haplotype blocks [93,94], and significant efforts are ongoing to describe genomic patterns of association in four ethnic groups of African, Asian, and European ancestry.…”

Section: The Future Looks Brightmentioning

confidence: 99%

Progress toward discerning the genetics of cleft lip

Lidral

Moreno

2005

Current Opinion in Pediatrics

111

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Purpose of review-Orofacial clefts are common birth defects with a known genetic component to their etiology. Most orofacial clefts are nonsyndromic, isolated defects, which can be separated into two different phenotypes: (1) cleft lip with or without cleft palate and (2) cleft palate only. Both are genetically complex traits, which has limited the ability to identify disease loci or genes. The purpose of this review is to summarize recent progress of human genetic studies in identifying causal genes for isolated or nonsyndromic cleft lip with or without cleft palate.Recent findings-The results of multiple genome scans and a subsequent meta-analysis have significantly advanced our knowledge by revealing novel loci. Furthermore, candidate gene approaches have identified important roles for IRF6 and MSX1. To date, causal mutations with a known functional effect have not yet been described.Summary-With the implementation of genome-wide association studies and inexpensive sequencing, future studies will identify disease genes and characterize both gene-environment and gene-gene interactions to provide knowledge for risk counseling and the development of preventive therapies.

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“…The etiology is very heterogeneous and includes both genetic and environmental factors. Strong associations have been found between nonsyndromic CL/P and CPO and most if not all human chromosomes, including chromosome 2 [Brewer et al, 1998[Brewer et al, , 1999Prescott et al, 2000;Marazita et al, 2002;Zeiger et al, 2003;Blanton et al, 2004]. Different genes or regions on chromosome 2 have been implicated, including the gene for transforming growth factor alpha (TGFA) at 2p13 for CL/P [Prescott et al, 2000], the proximal part of chromosome 2q for CL/P [Riegel and Schinzel, 2002], 2q32 for CPO [Brewer et al, 1998[Brewer et al, , 1999, and 2q37 for CL/P [Zeiger et al, 2003;Blanton et al, 2004].…”

Section: Discussionmentioning

confidence: 99%

A new case of 2q duplication supports either a locus for orofacial clefting between markers D2S1897 and D2S2023 or a locus for cleft palate only on chromosome 2q13‐q21

Õunap

Ilus

Laidre³

et al. 2005

American J of Med Genetics Pt A

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We report on a pure duplication of the proximal chromosome 2q in a 6.5‐year‐old boy with V‐shaped midline cleft palate and bifid uvula, posteriorly located tongue, and micrognathia (Pierre Robin sequence), celiac disease, failure to thrive, and developmental delay. Cytogenetic and FISH analysis indicated a duplication of chromosome 2q13‐q22. In general, pure proximal duplication or triplication of 2q is rare. The clinical features and chromosomal breakpoints of the 10 previously reported patients varied, and no common phenotype or proximal duplication/triplication 2q syndrome could be defined to date. However, based on four previous patients with different orofacial clefts and our case, a locus for orofacial clefting may be located at proximal 2q. The duplication/triplication comprised chromosome 2q13 in all five affected individuals including our patient. Our patient and three previous cases (two with cleft palate only (CPO) and one with cleft lip/palate (CL/P)) showed a cytogenetic breakpoint at 2q13, which could support the presence of a critical dominant gene disrupted by a common breakpoint, however, the fifth case with CPO showed different breakpoints, advocating against the disruption of a critical dominant gene and supporting that the overexpression of a gene(s) on chromosome 2q13‐q21 may cause cleft palate only (CPO) and Pierre Robin sequence. Hence, our findings support either the presence of one locus for orofacial clefting (CL/P, CPO, and Pierre Robin sequence) between markers D2S1897 (chromosome 2q12.2) and D2S2023 (chromosome 2q14.2), or alternatively the presence of a locus for CPO and Pierre Robin sequence on chromosome 2q13‐q21. © 2005 Wiley‐Liss, Inc.

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Evidence for linkage of nonsyndromic cleft lip with or without cleft palate to a region on chromosome 2

Cited by 32 publications

References 31 publications

Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations

Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations

Progress toward discerning the genetics of cleft lip

A new case of 2q duplication supports either a locus for orofacial clefting between markers D2S1897 and D2S2023 or a locus for cleft palate only on chromosome 2q13‐q21

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