Orofacial clefts (OFCs) are common (1 in 700 births) congenital malformations that include a cleft lip (CL) and cleft lip and palate (CLP). These OFC subtypes are also heterogeneous themselves, with the CL occurring on the left, right, or both sides of the upper lip. Unilateral CL and CLP have a 2:1 bias towards left-sided clefts, suggesting a nonrandom process. Here, we performed a study of left- and right-sided clefts within the CL and CLP subtypes to better understand the genetic factors controlling cleft laterality. We conducted genome-wide modifier analyses by comparing cases that had right unilateral CL (RCL; N = 130), left unilateral CL (LCL; N = 216), right unilateral CLP (RCLP; N = 416), or left unilateral CLP (LCLP; N = 638), and identified a candidate region on 4q28, 400 kb downstream from FAT4, that approached genome-wide significance for LCL versus RCL (p = 8.4 × 10⁻⁸). Consistent with its potential involvement as a genetic modifier of CL, we found that Fat4 exhibits a specific domain of expression in the mesenchyme of the medial nasal processes that form the median upper lip. Overall, these results suggest that the epidemiological similarities in left- to right-sided clefts in CL and CLP are not reflected in the genetic association results.

中文翻译：

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FAT4 被确定为口面侧裂的潜在调节剂

口面部裂 (OFC) 是常见的（每 700 名新生儿中有 1 名）先天性畸形，包括唇裂 (CL) 和唇腭裂 (CLP)。这些 OFC 亚型本身也是异质的，CL 发生在上唇的左侧、右侧或两侧。单侧 CL 和 CLP 对左侧裂隙的偏向为 2:1，表明非随机过程。在这里，我们对 CL 和 CLP 亚型内的左侧和右侧裂隙进行了研究，以更好地了解控制裂隙侧向性的遗传因素。我们通过比较具有右单侧 CL (RCL; N  = 130)、左单侧 CL (LCL; N  = 216)、右单侧 CLP (RCLP; N  = 416) 或左单侧 CLP的病例进行全基因组修饰分析。LCLP；N = 638)，并在 FAT4 下游 400 kb 的 4q28 上确定了一个候选区域，该区域接近 LCL 与 RCL 的全基因组显着性 ( p  = 8.4 × 10 ^-8 )。与其作为 CL 的遗传修饰剂的潜在参与一致，我们发现Fat4在形成中上唇的内侧鼻突的间充质中表现出特定的表达域。总体而言，这些结果表明 CL 和 CLP 中左右裂隙的流行病学相似性并未反映在遗传关联结果中。