The contribution of low-frequency variants to the genetic architecture of normal-range facial traits is unknown. We studied the influence of low-frequency coding variants (MAF < 1%) on multi-dimensional facial shape phenotypes in 2329 healthy Europeans. We used MultiSKAT o scan the exome for face-associated low-frequency variants in a gene-based manner. Seven genes (AR, CARS2, FTSJ1, HFE, LTB4R, TELO2, NECTIN1) were significantly associated with shape variation of the cheek, chin, nose and mouth areas. These genes displayed a wide range of phenotypic effects, with some impacting the full face and others affecting localized regions. The missense variant rs142863092 in NECTIN1 had a significant effect on chin morphology, and was predicted bioinformatically to be deleterious. NECTIN1 is an established craniofacial gene that underlies a human syndrome that includes a mandibular phenotype. We further showed that nectin1a mutations can affect zebrafish craniofacial development, with the size and shape of the mandibular cartilage altered in mutant animals. These Findings highlighted the role of low-frequency coding variants in normal-range facial variation.

中文翻译：

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低频编码变体对人脸形状的影响

低频变异对正常范围面部特征遗传结构的贡献尚不清楚。我们研究了2329名健康欧洲人中低频编码变体（MAF <1％）对多维面部形状表型的影响。我们使用MultiSKAT o以基于基因的方式扫描外显子组中与面部相关的低频变异。七个基因（AR，CARS2，FTSJ1，HFE，LTB4R，TELO2，NECTIN1）与脸颊，下巴，鼻子和嘴巴区域的形状变化显着相关。这些基因表现出广泛的表型效应，其中一些影响全脸，而另一些影响局部区域。NECTIN1中的错义变体rs142863092对下巴形态具有重大影响，并据生物信息学预测是有害的。NECTIN1是已建立的颅面基因，是包括下颌骨表型的人类综合症的基础。我们进一步表明，nectin1a突变可影响斑马鱼颅面发育，并且在突变动物中改变了下颌软骨的大小和形状。这些发现强调了低频编码变体在正常范围的面部变化中的作用。