Searching for Genes for Cleft Lip and/or Palate Based on Breakpoint Analysis of a Balanced Translocation t(9;17)(q32;q12)

Abstract

Objective-Identification of the breakpoints of disease-associated chromosome rearrangements can provide informative clues to a positional cloning approach for genes responsible for inherited diseases. Recently, we found a three-generation Japanese family segregating balanced chromosome translocation t(9;17)(q32;q12). One of the subjects had cleft lip and palate. We examined whether regions near the breakpoint could be associated with cleft lip and/or palate.Methods-We determined the breakpoints involved in the translocation by fluorescence in situ hybridization analysis and subsequent long-range polymerase chain reaction. In order to study the role of these disrupted regions in nonsyndromic cleft lip and/or palate, we performed mutation analysis and a haplotype-based transmission disequilibrium test using tagging single-nucleotide polymorphisms in the flanking regions of the breakpoints in white and Filipino nonsyndromic cleft lip and/or palate populations.Results-Sequence analysis demonstrated that two genes, SLC31A1 (solute carrier family 31 member 1) on chromosome 9 and CCL2 (chemokine ligand 2) on chromosome 17, were rearranged with the breaks occurring within their introns. It is interesting that SLC31A1 lies closed to BSPRY (B-box and SPRY domain), which is a candidate for involvement with cleft lip and/or palate. Some of the variants in BSPRY and CCL2 showed significant p values in the cleft lip and/or palate population compared with the control population. There was also statistically significant evidence of transmission distortion for haplotypes on both chromosomes 9 and 17.Conclusions-The data support previous reports that genes on chromosomal regions of 9q and 17q play an important role in facial development.

Genetics of cleft lip and cleft palate

“…Analysis of breakpoints in patients with balanced rearrangements has identified CLPTM1 [Yoshiura et al, 1998], SATB2 [FitzPatrick et al, 2003], SUMO1 [Alkuraya et al, 2006], and FGFR1 [Kim et al, 2005] as candidate genes for CL/P, and implicated 9q and 17q as potential risk loci [Machida et al, 2009]. In contrast, copy number variants (CNVs) and microdeletions are submicroscopic gains or losses of DNA segments ranging from kilobases to megabases.…”

Letters to the Editor

“…We read recently an excellent paper by Machida et al (2009). We were deeply impressed by this very up-to-date and enlighting paper related to genes of cleft lip and cleft palate.…”

“…In this paper, Machida et al demonstrated that two genes, SLC31A1 (solute carrier family 31 member 1) on chromosome 9 and CCL2 (chemokine ligand 2) on chromosome 17, were rearranged with the breaks occurring within their introns. SLC31A1 lies close to BSPRY (B-box and SPRYdomain), which is a candidate gene for involvement with cleft lip and/or palate (Machida et al, 2009).…”

Utilização da técnica de Open Array para investigação de genes associados a fendas labiopalatais em amostra da população brasileira

“…Os rearranjos genômicos são causados por recombinação imprópria de cromossomos e incluem deleções, duplicações, translocações, inversões e podem ocorrer dentro ou entre cromossomos. A análise de pontos de quebra em rearranjos equilibrados identificou os genes CLPTM1 (159), SATB2 (198), SUMO1 (199), e FGFR1 (94) como genes candidatos para fenda de lábio com ou sem fenda de palato, e implicou as regiões 9q e 17q como potenciais loci de risco (200).…”