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Birth Defects Res. 2019 Dec 11. doi: 10.1002/bdr2.1630. [Epub ahead of print]

PBX-WNT-P63-IRF6 pathway in nonsyndromic cleft lip and palate.

Author information

1
Department of Pediatrics, University of Texas Health Science Center McGovern Medical School at Houston, Houston, Texas.
2
Department of Diagnostic and Biomedical Sciences, University of Texas Health Science Center School of Dentistry at Houston, Houston, Texas.
3
Center for Craniofacial Research, University of Texas Health Science Center School of Dentistry at Houston, Houston, Texas.
4
Department of Endodontics, University of Texas Health Science Center School of Dentistry at Houston, Houston, Texas.
5
Department of Plastic Surgery, Texas Children's Hospital, Houston, Texas.
6
Boston Children's Hospital, Boston, Massachusetts.
7
Department of Pediatric Surgery, University of Texas Health Science Center McGovern Medical School at Houston, Houston, Texas.
8
Shriners Hospital for Children Houston, Houston, Texas.
9
Department of Pediatric Dentistry, University of Texas Health Science Center School of Dentistry at Houston, Houston, Texas.
10
Dr. John T. MacDonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida.

Abstract

Nonsyndromic cleft lip and palate (NSCLP) is one of the most common craniofacial anomalies in humans, affecting more than 135,000 newborns worldwide. NSCLP has a multifactorial etiology with more than 50 genes postulated to play an etiologic role. The genetic pathway comprised of Pbx-Wnt-p63-Irf6 genes was shown to control facial morphogenesis in mice and proposed as a regulatory pathway for NSCLP. Based on these findings, we investigated whether variation in PBX1, PBX2, and TP63, and their proposed interactions were associated with NSCLP. Fourteen single nucleotide variants (SNVs) in/nearby PBX1, PBX2, and TP63 were genotyped in 780 NSCLP families of nonHispanic white (NHW) and Hispanic ethnicities. Family-based association tests were performed for individual SNVs stratified by ethnicity and family history of NSCLP. Gene-gene interactions were also tested. A significant association was found for PBX2 rs3131300 and NSCLP in combined Hispanic families (p = .003) while nominal association was found for TP63 rs9332461 in multiplex Hispanic families (p = .005). Significant haplotype associations were observed for PBX2 in NHW (p = .0002) and Hispanic families (p = .003), and for TP63 in multiplex Hispanic families (.003). An independent case-control group was used to validate findings, and significant associations were found with PBX1 rs6426870 (p = .007) and TP63 rs9332461 (p = .03). Gene-gene interactions were detected between PBX1/PBX2/TP63 with IRF6 in NHW families, and between PBX1 with WNT9B in both NHW and Hispanic families (p < .0018). This study provides the first evidence for a role of PBX1 and PBX2, additional evidence for the role of TP63, and support for the proposed PBX-WNT-TP63-IRF6 regulatory pathway in the etiology of NSCLP.

PMID:
31825181
DOI:
10.1002/bdr2.1630

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