Association of MSX1 and TGFB3 with nonsyndromic clefting in humans

Am J Hum Genet. 1998 Aug;63(2):557-68. doi: 10.1086/301956.


Nonsyndromic cleft lip with or without cleft palate (CL/P) and nonsyndromic cleft palate only (CPO) are common congenital anomalies with significant medical, psychological, social, and economic ramifications. Both CL/P and CPO are examples of complex genetic traits. There exists sufficient evidence to hypothesize that disease loci for CL/P and CPO can be identified by a candidate-gene linkage-disequilibrium (LD) strategy. Candidate genes for clefting, including TGFA, BCL3, DLX2, MSX1, and TGFB3, were screened for LD with either CL/P or CPO in a predominantly Caucasian population, with both case-control- and nuclear-family-based approaches. Previously reported LD for TGFA with both CL/P and CPO could not be confirmed, except in CL/P patients with a positive family history. Also, in contrast to previous studies, no LD was found between BCL3 and either CL/P or CPO. Significant LD was found between CL/P and both MSX1 and TGFB3 and between CPO and MSX1, suggesting that these genes are involved in the pathogenesis of clefting. In addition, a mutation search in the genes DLX2, MSX1, and TGFB3 was performed in 69 CPO patients and in a subset of the CL/P patients. No common mutations were found in the coding regions of these genes; however, several rare variants of MSX1 and TGFB3 were found that may alter the latters' normal function. These results form the basis for future research, including (a) mutation searches in the MSX1 and TGFB3 genes in Caucasian CL/P patients and (b) extension of the search for MSX1 mutations in CPO patients to the noncoding regions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Substitution
  • Case-Control Studies
  • Cleft Lip / genetics*
  • Cleft Palate / genetics*
  • Exons
  • Genetic Markers
  • Genetic Variation
  • Homeodomain Proteins / genetics*
  • Humans
  • Introns
  • Iowa
  • Linkage Disequilibrium*
  • MSX1 Transcription Factor
  • Mutation*
  • Nuclear Family
  • Open Reading Frames
  • Point Mutation
  • Transcription Factors*
  • Transforming Growth Factor beta / genetics*
  • Whites / genetics


  • Genetic Markers
  • Homeodomain Proteins
  • MSX1 Transcription Factor
  • Transcription Factors
  • Transforming Growth Factor beta