Abstract：
OBJECTIVE: Tooth agenesis (TA) is among the most common malformations in humans. Although several causative mutations have been described, the genetic cause often remains elusive. Here, we test whether whole genome sequencing (WGS) could bridge this diagnostic gap.
METHODS: In four families with TA, we assessed the dental phenotype using the Tooth Agenesis Code after intraoral examination and radiographic and photographic documentation. We performed WGS of index patients and subsequent segregation analysis.
RESULTS: We identified two variants of uncertain significance (a potential splice variant in PTH1R, and a 2.1 kb deletion abrogating a non-coding element in FGF7) and three pathogenic variants: a novel frameshift in the final exon of PITX2, a novel deletion in PAX9, and a known nonsense variant in WNT10A. Notably, the FGF7 variant was found in the patient, also featuring the WNT10A variant. While mutations in PITX2 are known to cause Axenfeld-Rieger syndrome 1 (ARS1) predominantly featuring ocular findings, accompanied by dental malformations, we found the PITX2 frameshift in a family with predominantly dental and varying ocular findings.
CONCLUSIONS: Severe TA predicts a genetic cause identifiable by WGS. Final exon PITX2 frameshifts can cause a predominantly dental form of ARS1.
METHODS: In four families with TA, we assessed the dental phenotype using the Tooth Agenesis Code after intraoral examination and radiographic and photographic documentation. We performed WGS of index patients and subsequent segregation analysis.
RESULTS: We identified two variants of uncertain significance (a potential splice variant in PTH1R, and a 2.1 kb deletion abrogating a non-coding element in FGF7) and three pathogenic variants: a novel frameshift in the final exon of PITX2, a novel deletion in PAX9, and a known nonsense variant in WNT10A. Notably, the FGF7 variant was found in the patient, also featuring the WNT10A variant. While mutations in PITX2 are known to cause Axenfeld-Rieger syndrome 1 (ARS1) predominantly featuring ocular findings, accompanied by dental malformations, we found the PITX2 frameshift in a family with predominantly dental and varying ocular findings.
CONCLUSIONS: Severe TA predicts a genetic cause identifiable by WGS. Final exon PITX2 frameshifts can cause a predominantly dental form of ARS1.
摘要：
目的：牙齿发育不全（TA）是人类最常见的畸形之一。尽管已经描述了几种致病突变，遗传原因往往仍然难以捉摸。这里,我们测试了全基因组测序(WGS)是否可以弥补这一诊断差距.
方法：在有TA的四个家庭中，我们在口内检查和影像学和摄影记录后,使用牙机构代码评估了牙齿表型.我们对索引患者进行了WGS和随后的隔离分析。
结果：我们确定了两个具有不确定意义的变体（PTH1R中的潜在剪接变体，和2.1kb的缺失消除了FGF7中的非编码元件）和三个致病变体：PITX2最后外显子中的新移码，PAX9中的新缺失和WNT10A中的已知无义变体。值得注意的是,在病人身上发现了FGF7变异体,还具有WNT10A变体。虽然已知PITX2中的突变会导致Axenfeld-Rieger综合征1（ARS1）主要以眼部表现为特征，伴有牙齿畸形，我们发现PITX2移码发生在一个以牙齿和不同眼部表现为主的家庭中.
结论：严重TA预测WGS可识别的遗传原因。最终外显子PITX2移码可导致ARS1的主要牙齿形式。
方法：在有TA的四个家庭中，我们在口内检查和影像学和摄影记录后,使用牙机构代码评估了牙齿表型.我们对索引患者进行了WGS和随后的隔离分析。
结果：我们确定了两个具有不确定意义的变体（PTH1R中的潜在剪接变体，和2.1kb的缺失消除了FGF7中的非编码元件）和三个致病变体：PITX2最后外显子中的新移码，PAX9中的新缺失和WNT10A中的已知无义变体。值得注意的是,在病人身上发现了FGF7变异体,还具有WNT10A变体。虽然已知PITX2中的突变会导致Axenfeld-Rieger综合征1（ARS1）主要以眼部表现为特征，伴有牙齿畸形，我们发现PITX2移码发生在一个以牙齿和不同眼部表现为主的家庭中.
结论：严重TA预测WGS可识别的遗传原因。最终外显子PITX2移码可导致ARS1的主要牙齿形式。
