Data for: "Intra-familial phenotype variation in hypoplastic amelogenesis imperfecta under a complex genetic component: a family report, whole-exome sequencing, and literature review"

Supplementary material of exome analysis of the individuals investigated in this study.

Introduction: Amelogenesis imperfecta (AI) refers to a group of conditions characterized by abnormalities in the development or function of the tooth enamel. Clinical manifestations include different forms and grades of enamel frailty, associated with sensitivity, tooth fractures, stains, abnormal dental form, absent teeth, etc. AI is genetically heterogeneous and over 70 genes have already been associated with autosomal dominant and recessive, X-linked, and oligogenic inheritance. Objective: to search for genetic variants in an AI family. Methodology: Here, we describe the clinical findings of an AI family, composed of five persons, four affected (the father and three daughters) and the unaffected mother. AI segregation pattern suggests dominant, X-linked inheritance. Genetic variants were screened using Whole Exome Sequencing. Results: The initial bioinformatic analysis was conducted in Qiagen QCI and the variant selection criteria used were to be present in the four affected family members and absent in the unaffected mother. Search terms used were “amelogenesis imperfecta”, tooth, and enamel. Several software were used to classify variants according to pathogenicity. Candidate variants emerged in six genes. Three of these variants were detected in autosomal genes: NM_031889.3(ENAM):c.1726T>C (p.F576L), NM_022168.4(IFIH1):c.1764dupA, (p.A589fs*21), and NM_032383.5(HPS3):c.1897A>T (p.M633L). Three variants were detected in X-linked genes: NM_006150.5(PRICKLE3):c.8C>G (p.A3G), NM_004484.4(GPC3):c.584A>G (p.N195S), and NM_152787.5(TAB3):c.1936G>A (p.V646M). None of these variants were classified as definitely likely pathogenic/pathogenic in AI. Discussion: Of these genes, only ENAM has been associated with AI previously, but IFIH1, PRICKLE3, and GPC3 are associated with dental/enamel development. The relatively large number of candidate genes/genetic variants detected may reflect an oligogenic component already proposed for AI. Conclusions: this study provides a set of new candidate genes and genetic variants for AI. Despite sharing the variants, AI-affected persons in this family show great phenotypic variation, suggesting the contribution of non-shared genetic or environmental components.

本研究纳入受试者的外显子组分析补充材料。

引言：成釉不全（Amelogenesis imperfecta, AI）是一组以牙釉质发育或功能异常为特征的疾病群。其临床表现为不同类型与程度的牙釉质脆弱，可伴发牙敏感、牙折、牙着色异常、牙形态异常、缺牙等症状。成釉不全具有遗传异质性，目前已有超过70个基因与常染色体显性、常染色体隐性、X连锁以及寡基因遗传模式的成釉不全相关。

研究目的：对一个成釉不全家系开展遗传变异筛查。

研究方法：本研究描述了一个共5名成员的成釉不全家系的临床表型：包括4名患者（父亲与三名女儿）及1名表型正常的母亲。家系中AI的传递模式符合显性X连锁遗传特征。研究采用全外显子组测序技术对遗传变异进行筛查。初始生物信息学分析在Qiagen QCI平台完成，变异筛选标准为：该变异需同时存在于4名受累家系成员中，且在表型正常的母亲中未检出。本次检索使用的关键词为"amelogenesis imperfecta"、"tooth"及"enamel"。研究采用多款软件依据致病性对变异进行分级。最终在6个基因中筛选到候选变异：其中3个位于常染色体基因：NM_031889.3(ENAM):c.1726T>C (p.F576L)、NM_022168.4(IFIH1):c.1764dupA (p.A589fs*21) 及NM_032383.5(HPS3):c.1897A>T (p.M633L)；另外3个位于X连锁基因：NM_006150.5(PRICKLE3):c.8C>G (p.A3G)、NM_004484.4(GPC3):c.584A>G (p.N195S) 及NM_152787.5(TAB3):c.1936G>A (p.V646M)。上述变异均未被归类为成釉不全相关的明确可能致病/致病性变异。

讨论：上述基因中，仅ENAM既往已被证实与成釉不全相关，而IFIH1、PRICKLE3及GPC3均与牙/牙釉质发育过程密切相关。本次筛查到的候选基因与遗传变异数量相对较多，这可能印证了成釉不全存在寡基因遗传模式的已有假说。

结论：本研究为成釉不全提供了一批新的候选基因与遗传变异。尽管该家系的AI患者共享上述变异，但患者间仍存在显著的表型异质性，提示非共享的遗传或环境因素参与了疾病表型的调控。