Studies of human chromosomal aberrations and knockout (KO) mice have suggested SATB2 as a candidate gene for a human malformation syndrome of craniofacial patterning and brain development. Of 59 unrelated patients with craniofacial dysmorphism, with or without mental retardation, one 36-year-old man had a nonsynonymous mutation in SATB2. The affected individual exhibited craniofacial dysmorphisms including cleft palate, generalized osteoporosis, profound mental retardation, epilepsy and a jovial personality. He carries a de novo germline nonsense mutation (c.715C>T, p.R239X) in the exon 6 of SATB2. Expression studies showed that the mutant RNA was stable, expected to produce a truncated protein predicted to retain its dimerization domain and exert a dominant negative effect. This new syndrome is the first determined to result from mutation of a gene within the family that encodes nuclear matrix-attachment region (MAR) proteins.

Background: Previous data have shown an association between DNA sequence variants in the IRF6 gene and an increased risk of non-syndromic cleft lip with or without cleft palate (CL/P) in some populations. Objective: To investigate Thai CL/P patients and relative for a 820GRA polymorphism. Subjects: 192 CL/P Thai patients, 177 of their mothers, 73 of their fathers, and 278 controls. Results: There were significant differences in the frequency distributions of both genotypes (p = 0.02) and alleles (p = 0.04) among probands as compared with the control group. The odds ratio calculated for the patients having the GG genotype compared with the other two genotypes (GA and AA) was 1.67 (95% confidence interval, 1.13 to 2.47). This pattern is consistent with a recessive effect of the G allele. No association between any of the parents' genotypes and CL/P was found. The IRF6 820GRA was responsible for 16.7% of the genetic contribution to CL/P. Conclusions: The findings confirm that IRF6 820GRA is associated with CL/P.

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Previous studies observed that MSX1 mutations could contribute to nonsyndromic cleft lip with or without cleft palate (CL/P) in some populations. Of the proposed pathogenic mutations, the P147Q variant was predominant in Vietnamese and present in Filipino populations. We investigated whether MSX1 mutations also contribute to nonsyndromic CL/P in the Thai population. Specifically, we performed mutation analysis covering all the coding regions of the MSX1 gene for 100 Thai patients with nonsyndromic CL/P. A total of eight variant sites were identified. Six were in coding regions, including four nonsynonymous changes, 101C > G (A34G), 440C > A (P147Q), 799G > T (G267C), and 832C > T (P278S). The G267C and P278S variants were predicted to be "probably damaging" by PolyPhen, changed themselves as potential exonic splicing enhancers for serine/arginine-rich proteins, and were not present in 162 control individuals of Thai ethnic background. Unlike all of the previously reported potential missense mutations in MSX1, these two novel potential mutations were found in exon 2 on the C-terminal side of the homeodomain protein. Moreover, in contrast to previous reports, we found the P147Q variant in 8 out of 100 Thai controls and an association between the variant and CL/P in our population could not be detected, suggesting that it is not pathogenic. Our data support that MSX1 mutations are found in 2% of cases of CL/P and should be considered for genetic counseling implications, but suggest that the P147Q variant is not pathogenic.

Mutations in the TBX22 gene underlie an X-linked malformation syndrome with cleft palate (CP) and ankyloglossia. Its mutations also result in non-syndromic CP in some populations. To investigate whether mutations in TBX22 play a part in the formation of non-syndromic CP in the Thai population, we performed mutation analysis covering all the coding regions of the TBX22 gene in 53 unrelated Thai patients with non-syndromic CP. We identified four potentially pathogenic mutations, 359G-->A (R120Q), 452G-->T (R151L), 1166C-->A (P389Q), and 1252delG in four different patients. All mutations were not detected in at least 112 unaffected ethnic-matched control chromosomes and had never been previously reported. R120Q and R151L, found in two sporadic cases, were located in the DNA binding T-box domain. P389Q and 1252delG, found in two familial cases, were at the carboxy-terminal region, which has never been described. Our study indicates that TBX22 mutations are responsible for a significant proportion of Thai non-syndromic CP cases confirming its importance as a frequent cause of non-syndromic CP across different populations.