Teruyuki Niimi

Mutations in BMP4 Are Associated with Subepithelial, Microform, and Overt Cleft Lip

Cleft lip with or without cleft palate (CL/P) is a complex trait with evidence that the clinical spectrum includes both microform and subepithelial lip defects. We identified missense and nonsense mutations in the BMP4 gene in 1 of 30 cases of microform clefts, 2 of 87 cases with subepithelial defects in the orbicularis oris muscle (OOM), 5 of 968 cases of overt CL/P, and 0 of 529 controls. These results provide confirmation that microforms and subepithelial OOM defects are part of the spectrum of CL/P and should be considered during clinical evaluation of families with clefts. Furthermore, we suggest a role for BMP4 in wound healing.

Replication of genome wide association identified candidate genes confirm the role of common and rare variants in PAX7 and VAX1 in the etiology of nonsyndromic CL(P).

Following recent genome wide association studies (GWAS), significant genetic associations have been identified for several genes with nonsyndromic cleft lip with or without cleft palate (CL(P)). To replicate two of these GWAS signals, we investigated the role of common and rare variants in the PAX7 and VAX1 genes. TaqMan genotyping was carried out for SNPs in VAX1 and PAX7 and transmission disequilibrium test (TDT) was performed to test for linkage and association in each population. Direct sequencing in and around the PAX7 and VAX1 genes in 1,326 individuals of European and Asian ancestry was done. The TDT analysis showed strong associations with markers in VAX1 (rs7078160, P = 2.7E−06 and rs475202, P = 0.0002) in a combined sample of Mongolian and Japanese CL(P) case–parent triads. Analyses using parent‐of‐origin effects showed significant excess transmission of the minor allele from both parents with the effect in the mothers (P = 6.5E−05, OR (transmission) = 1.91) more striking than in the fathers (P = 0.004, OR (transmission) = 1.67) for VAX1 marker rs7078160 in the combined Mongolian and Japanese samples when all cleft types were combined. The rs6659735 trinucleotide marker in PAX7 was significantly associated with all the US cleft groups combined (P = 0.007 in all clefts and P = 0.02 in CL(P)). Eight rare missense mutations found in PAX7 and two rare missense mutations in VAX1. Our study replicated previous GWAS findings for markers in VAX1 in the Asian population, and identified rare variants in PAX7 and VAX1 that may contribute to the etiology of CL(P). Determining the role of rare variants clearly warrants further investigation.

Effects of a long-term volunteer surgical program in a developing country: the case in Vietnam from 1993 to 2003.

Objective: This study evaluates the activities of the Japanese Cleft Palate Foundation from 1993 to 2003 in southern Vietnam. Design: We assessed trends associated with patient age at first operation for primary lip repair and palate repair by using medical records of the patients. Participants: This study consisted of 790 patients with nonsyndromic cleft lip and/or palate (CL/P). Results: The median patient age for lip repair was reduced from 14.0 years in 1993 to 1.3 years by 2003. For palate repair, the median age was reduced from 13.5 years in 1993 to 5.0 years in 1999 through 2003. The age distributions of both lip and palate repair in the later years became smaller than the age distributions in 1993. The number of adult patients declined throughout the period. Conclusions: The Japanese Cleft Palate Foundation contributed to lowering the age at first operation for CL/P and to reducing the number of adult patients in Ben Tre province, southern Vietnam. However, appropriate supports will be necessary to maintain CL/P treatment and to improve locally supported health care for patients with CL/P.

Association of MEOX2 Polymorphism with Nonsyndromic Cleft Palate Only in a Vietnamese population

To evaluate the association between the single nucleotide polymorphism (SNP) rs227493 in the MEOX2 gene and nonsyndromic cleft palate only, this research was conducted as a case–control study by comparing a nonsyndromic cleft palate only group with an independent, healthy, and unaffected control group who were both examined by specialists. Based on clinical examination and medical records, we analyzed a total of 570 DNA samples, including 277 cases and 293 controls, which were extracted from dry blood spot samples collected from both the Odonto and Maxillofacial Hospital in Ho Chi Minh City and Nguyen Dinh Chieu Hospital in Ben Tre province, respectively. The standard procedures of genotyping the specific SNP (rs2237493) for MEOX2 were performed on a StepOne Realtime PCR system with TaqMan SNP Genotyping Assays. Significant statistical differences were observed in allelic frequencies (allele T and allele G) between the non‐syndromic cleft palate only and control groups in female subjects, with an allelic odds ratio of 1.455 (95% confidence interval: 1.026–2.064) and P < 0.05. These study findings suggest that nonsyndromic isolated cleft palate might be influenced by variation of MEOX2, especially SNP rs2237493 in Vietnamese females.