Class III malocclusion is a common dentofacial deformity. The underlying genetic alteration is largely unclear. In this study, we sought to determine the genetic etiology for Class III malocclusion. A four‐generation pedigree of Class III malocclusion was recruited for exome sequencing analyses. The likely causative gene was verified via Sanger sequencing in an additional 90 unrelated sporadic Class III malocclusion patients. We identified a rare heterozygous variant in endoplasmic reticulum lectin 1 (ERLEC1 ; NM_015701.4(ERLEC1_v001):c.1237C>T, p.(His413Tyr), designated as ERLEC1‐m in this article) that cosegregated with the deformity in pedigree members and three additional rare missense heterozygous variants (c.419C>G, p.(Thr140Ser), c.419C>T, p.(Thr140Ile), and c.1448A>G, p.(Asn483Ser)) in 3 of 90 unrelated sporadic subjects. Our results showed that ERLEC1 is highly expressed in mouse jaw osteoblasts and inhibits osteoblast proliferation. ERLEC1‐m significantly enhanced this inhibitory effect of osteoblast proliferation. Our results also showed that the proper level of ERLEC1 expression is crucial for proper osteogenic differentiation. The ERLEC1 variant identified in this study is likely a causal mutation of Class III malocclusion. Our study reveals the genetic basis of Class III malocclusion and provides insights into the novel target for clinical management of Class III malocclusion, in addition to orthodontic treatment and orthodontic surgery.

中文翻译：

---

通过外显子组测序鉴定 III 类错牙合患者中 ERLEC1 的致病变异。

III级错牙合是一种常见的牙面畸形。潜在的遗传改变在很大程度上尚不清楚。在这项研究中，我们试图确定 III 类错牙合的遗传病因。招募了 III 类错牙合的四代谱系进行外显子组测序分析。在另外 90 名不相关的散发性 III 类错牙合患者中，通过 Sanger 测序验证了可能的致病基因。我们在内质网凝集素 1 ( ERLEC1 ; NM_015701.4(ERLEC1_v001):c.1237C>T, p.(His413Tyr) 中鉴定出一种罕见的杂合变异体，命名为ERLEC1-m在这篇文章中）与谱系成员的畸形和另外三个罕见的错义杂合变体（c.419C>G、p.(Thr140Ser)、c.419C>T、p.(Thr140Ile)和c.1448A>G共分离） , p.(Asn483Ser)) 在 90 个不相关的零星主题中的 3 个。我们的结果表明ERLEC1在小鼠颌骨成骨细胞中高表达并抑制成骨细胞增殖。ERLEC1-m显着增强了这种成骨细胞增殖的抑制作用。我们的结果还表明，适当水平的 ERLEC1 表达对于适当的成骨分化至关重要。该ERLEC1本研究中发现的变异很可能是 III 类错牙合的因果突变。我们的研究揭示了 III 类错牙合的遗传基础，并提供了对 III 类错牙合临床管理新目标的见解，以及正畸治疗和正畸手术。