Article

European Journal of Human Genetics (2009) 17, 195–204; doi:10.1038/ejhg.2008.149; published online 20 August 2008

Genomic screening identifies novel linkages and provides further evidence for a role of MYH9 in nonsyndromic cleft lip and palate

Brett T Chiquet1,2, Syed S Hashmi1,3, Robin Henry1, Amber Burt4, John B Mulliken5, Samuel Stal6, Molly Bray7, Susan H Blanton4 and Jacqueline T Hecht1

  1. 1Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX, USA
  2. 2University of Texas Dental Branch at Houston, Houston, TX, USA
  3. 3University of Texas School of Public Health, Houston, TX, USA
  4. 4Miami Institute for Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA
  5. 5Department of Plastic Surgery, Children's Hospital, Boston, MA, USA
  6. 6Division of Plastic Surgery, Texas Children's Hospital, Houston, TX, USA
  7. 7Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

Correspondence: Dr JT Hecht, Department of Pediatrics, University of Texas Houston Medical School, 6431 Fannin St MSB 3.136, PO Box 20708, Houston, TX 77225, USA. Tel: 1 713 500 5764; Fax: 1 713 500 5689; E-mail: jacqueline.t.hecht@uth.tmc.edu

Received 4 April 2008; Revised 15 July 2008; Accepted 16 July 2008; Published online 20 August 2008.

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Abstract

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth anomaly that requires prolonged multidisciplinary rehabilitation. Although variation in several genes has been identified as contributing to NSCLP, most of the genetic susceptibility loci have yet to be defined. To identify additional contributory genes, a high-throughput genomic scan was performed using the Illumina Linkage IVb Panel platform. We genotyped 6008 SNPs in nine non-Hispanic white NSCLP multiplex families and a single large African-American NSCLP multiplex family. Fourteen chromosomal regions were identified with LOD>1.5, including six regions not previously reported. Analysis of the data from the African-American and non-Hispanic white families revealed two likely chromosomal regions: 8q21.3–24.12 and 22q12.2–12.3 with LOD scores of 2.98 and 2.66, respectively. On the basis of biological function, syndecan 2 (SDC2) and growth differentiation factor 6 (GDF6) in 8q21.3–24.12 and myosin heavy-chain 9, non-muscle (MYH9) in 22q12.2–12.3 were selected as candidate genes. Association analyses from these genes yielded marginally significant P-values for SNPs in SDC2 and GDF6 (0.01≤P<0.05). Evidence for an altered transmission was found for four MYH9 SNPs (P<0.01). SNP rs1002246 exhibited altered transmission by all analytic methods. However, analysis of two SNP MYH9 haplotypes did not identify a single high-risk haplotype. Our results confirm a previous report that 8q21.3–24.12 may harbor a clefting gene and identify 22q12.2–12.3 as a new candidate region that contains MYH9. Most importantly, we confirm the previous report of an association with MYH9.

Keywords:

cleft lip and palate, genome scan, SDC2, GDF6, MYH9