Analysis of sequence data to identify potential risk variants for oral clefts in multiplex families

Emily R. Holzinger, Qing Li, Margaret M. Parker, Jacqueline B. Hetmanski, Mary L. Marazita, Elisabeth Mangold, Kerstin U. Ludwig, Margaret A. Taub, Ferdouse Begum, Jeffrey C. Murray, Hasan Albacha-Hejazi, Khalid Alqosayer, Giath Al-Souki, Abdullatiff Albasha Hejazi, Alan F. Scott, Terri H. Beaty, Joan E. Bailey-Wilson

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Background: Nonsyndromic oral clefts are craniofacial malformations, which include cleft lip with or without cleft palate. The etiology for oral clefts is complex with both genetic and environmental factors contributing to risk. Previous genome-wide association (GWAS) studies have identified multiple loci with small effects; however, many causal variants remain elusive. Methods: In this study, we address this by specifically looking for rare, potentially damaging variants in family-based data. We analyzed both whole exome sequence (WES) data and whole genome sequence (WGS) data in multiplex cleft families to identify variants shared by affected individuals. Results: Here we present the results from these analyses. Our most interesting finding was from a single Syrian family, which showed enrichment of nonsynonymous and potentially damaging rare variants in two genes: CASP9 and FAT4. Conclusion: Neither of these candidate genes has previously been associated with oral clefts and, if confirmed as contributing to disease risk, may indicate novel biological pathways in the genetic etiology for oral clefts.

Original languageEnglish (US)
Pages (from-to)570-579
Number of pages10
JournalMolecular Genetics and Genomic Medicine
Issue number5
StatePublished - Sep 2017


  • DNA sequence data analysis
  • genetic risk variants
  • oral clefts
  • rare variants
  • statistical genetics

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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