Schultz R E, Cooper M E, Daack-Hirsch S, Shi M, Nepomucena B, Graf K A, O'Brien E K, O'Brien S E, Marazita M L, Murray J C
Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA.
Am J Med Genet A. 2004 Feb 15;125A(1):17-22. doi: 10.1002/ajmg.a.20424.
Cleft lip with or without cleft palate (CL/P) is a congenital anomaly with variable birth prevalence based on geographic origins, with the highest rates commonly found in Asian populations. About 70% of cases are nonsyndromic (NS), in which the affected individual has no other abnormalities. NS CL/P is a complex disorder with genetic and environmental effects and no specific genetic loci yet confirmed. Fifteen candidate regions were examined for linkage to NS CL/P. Regions were chosen based on previous suggestive linkage and/or association in human families, or suggestive animal model data. Polymorphic markers in these regions were genotyped for analysis on 36 Filipino families comprised of 126 affected and 218 unaffected individuals. An additional 70 families with 149 affecteds were used for replication of suggestive results. Parametric (LOD score) and nonparametric (SIMIBD) linkage analyses were performed as well as transmission disequilibrium test (TDT) analysis. Five markers yielded suggestive results from the 36 families. The parametric LOD scores for the MSX1-CA and D4S1629 were >1.0 and the SIMIBD P values for D6S1029 and RFC1 are suggestive (<0.06), while the SIMIBD P value of 0.01 for TGFA was significant. Since the Msx1 mouse knockout has cleft palate and MSX1 mutations have been found in rare cases of syndromic CL/P, this locus is especially plausible for linkage. Previous studies have also found linkage of NS CL/P to 4q31 and 6p23. These regions contain several candidate genes, including AP2 at 6p23 and FGF2, BMPR1B, and MADH1 at 4q31. TGFA has both linkage and linkage disequilibrium data supporting it as a candidate gene for NS CL/P. While no region was definitively confirmed for linkage to NS CL/P, the data do support further investigation using larger sample sizes and candidate gene studies at 2p13.2, 4p16.2, 4q31, 6p23, and 16q22-24.
唇裂伴或不伴腭裂(CL/P)是一种先天性畸形,其出生患病率因地理区域而异,亚洲人群中的患病率通常最高。约70%的病例为非综合征性(NS),即受影响个体无其他异常。NS CL/P是一种具有遗传和环境影响的复杂疾病,尚未确认特定的基因位点。对15个候选区域进行了与NS CL/P的连锁分析。这些区域是根据人类家系中先前提示性的连锁和/或关联,或提示性的动物模型数据选择的。对这些区域中的多态性标记进行基因分型,以分析36个菲律宾家庭,这些家庭由126名受影响个体和218名未受影响个体组成。另外70个家庭(含149名受影响个体)用于重复提示性结果。进行了参数化(LOD评分)和非参数化(SIMIBD)连锁分析以及传递不平衡检验(TDT)分析。36个家庭中有5个标记产生了提示性结果。MSX1-CA和D4S1629的参数化LOD评分>1.0,D6S1029和RFC1的SIMIBD P值具有提示性(<0.06),而TGFA的SIMIBD P值为0.01具有显著性。由于Msx1基因敲除小鼠有腭裂,且在罕见的综合征性CL/P病例中发现了MSX1突变,因此该基因座特别有可能存在连锁关系。先前的研究还发现NS CL/P与4q31和6p23存在连锁关系。这些区域包含几个候选基因,包括6p23处的AP2以及4q31处的FGF2、BMPR1B和MADH1。TGFA既有连锁分析数据,也有连锁不平衡数据支持其作为NS CL/P的候选基因。虽然没有区域被明确确认为与NS CL/P存在连锁关系,但这些数据确实支持使用更大样本量以及对2p13.2、4p16.2、4q31、6p23和16q22 - 24进行候选基因研究来进一步调查。
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