Lidral A C, Romitti P A, Basart A M, Doetschman T, Leysens N J, Daack-Hirsch S, Semina E V, Johnson L R, Machida J, Burds A, Parnell T J, Rubenstein J L, Murray J C
Department of Orthodontics, Ohio State University, Columbus, USA.
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.
非综合征性唇裂伴或不伴腭裂（CL/P）以及仅非综合征性腭裂（CPO）是常见的先天性异常，具有重大的医学、心理、社会和经济影响。CL/P和CPO都是复杂遗传性状的例子。有足够的证据推测，CL/P和CPO的疾病基因座可通过候选基因连锁不平衡（LD）策略来识别。采用病例对照法和基于核心家庭的方法，在以白种人为主的人群中，对包括TGFA、BCL3、DLX2、MSX1和TGFB3在内的腭裂候选基因进行了与CL/P或CPO的LD筛查。之前报道的TGFA与CL/P和CPO的LD无法得到证实，除了有阳性家族史的CL/P患者。此外，与之前的研究不同，未发现BCL3与CL/P或CPO之间存在LD。在CL/P与MSX1和TGFB3之间以及CPO与MSX1之间发现了显著的LD，这表明这些基因参与了腭裂的发病机制。此外，对69例CPO患者和部分CL/P患者的DLX2、MSX1和TGFB3基因进行了突变搜索。在这些基因的编码区未发现常见突变；然而，发现了MSX1和TGFB3的几个罕见变体，可能会改变它们的正常功能。这些结果构成了未来研究的基础，包括（a）对白种人CL/P患者的MSX1和TGFB3基因进行突变搜索，以及（b）将CPO患者中MSX1突变的搜索扩展到非编码区。
