遗传性骨性Ⅲ类错颌家系的全外显子组测序分析发现ADAMTSL1基因的新位点错义突变

The whole exome sequencing and analysis for a hereditary skeletal class Ⅲ malocclusion family pedigree finds a novel locus missense mutation in the ADAMTSLI gene

目的本研究旨在为遗传性骨性Ⅲ类错颌的风险基因突变及复杂遗传背景提供更多依据,进而可以为再生风险的产前诊断提供参考。方法对1个家族性骨性Ⅲ类错颌家系中患者进行全外显子组测序,设置合理条件对变异的注释进行筛选,并筛选下颌前突或骨性Ⅲ类错颌相关基因突变。对疾病相关基因突变进行进一步的生物信息学分析。Sanger测序验证患者的疾病相关基因突变并检测核心家庭成员的基因。结果在患者Ⅲ3、Ⅳ2的所有变异中,采用3个条件(突变有害性为高级,且突变质量值为高度或中度,且在HGMD数据库中突变涉及下颌前突)筛选后,仅发现ADAMTSL1基因的c.G1696A错义突变。这个基因突变位点是本研究首次报道的。该新位点(p.E566K)位于ADAMTSL1蛋白的关键结构功能域。多数软件预测该基因新位点突变为有害。该基因突变为常染色体显性遗传,但外显率不完全。结论本研究建立了从全外显子组测序结果中筛选下颌前突或骨性Ⅲ类错颌相关基因的合理、可行方法,具有实际推广应用价值。本研究报道了与骨性Ⅲ类错颌相关的ADAMTSL1基因的新位点错义突变。本研究结果可以为遗传性骨性Ⅲ类错颌的风险基因突变提供更多依据,进而可以为家系中再生风险的产前诊断提供参考。

Objective The purpose of this study is to provide more evidence for the risk genes and complex genetic background of hereditary skeletal class Il malocclusion,and then to provide a reference for prenatal diagnosis of regeneration risk.Methods Whole exome sequencing(WES)was performed on patients in a familial skeletal class II malocclusion family pedigree,and reasonable conditions were set to screen the variant annotations,and the gene mutations associated to mandibular protrusion or skeletal class Ⅱ malocclusion were screened.Further bioinformatic analysis of disease-associated gene mutations was performed.Sanger sequencing was used to verify disease-associated genetic mutations in patients and to detect genes in the main family members.Results Among all the variants of patients Ⅲ3 and IV2,after screened by the three conditions(the deleteriousness of the mutation was high,and the quality of the mutation was high or moderate,and the mutation was associated to mandibular protrusion in the HGMD database),only the c.G1696A missense mutation of ADAMTSL1 gene was found.This gene mutation locus was reported for the first time in this study.The new locus(p.E566K)was located in the key structural and functional domain of ADAMTSL1 protein.And majority of softwares predicted that the new locus mutation of this gene was harmful.This gene mutation was autosomal dominant,but with incomplete penetrance.Conclusion This study established a reasonable and feasible method for screening mandibular protrusion or skeletal class Ⅰ malocclusion associated genes from the results of whole-exome sequencing,which will have practical application value.This study reported a novel locus missense mutation in the ADAMTSLI gene associated with skeletal class Ⅱ malocclusion.The results of this study may provide more evidence for the risk gene mutations of hereditary skeletal class Ⅲ malocclusion,and then provide a reference for prenatal diagnosis of reproductive risk in the family pedigrees.