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

Célia Regina Moreira Lanza; Artur Melo Rodrigues; Iasmin Fonseca Tolentino Mascarenhas; Talita Roberta Ferreira de Souza; Matheus Oliveira Reis; Felipe Morando Avelar; Maria Raquel Santos Carvalho; Vasco Ariston Carvalho de Azevedo; Debmalya Barh

doi:10.1590/1678-7757-2024-0489

Authors

Célia Regina Moreira Lanza Universidade Federal de Minas Gerais, Faculdade de Odontologia, Departamento de Cirurgia Clínica e Patologia, Belo Horizonte, MG https://orcid.org/0000-0001-5893-2597
Artur Melo Rodrigues Universidade Federal de Minas Gerais, Faculdade de Medicina, Belo Horizonte, MG https://orcid.org/0009-0004-7072-8643
Iasmin Fonseca Tolentino Mascarenhas Universidade Federal de Minas Gerais, Faculdade de Odontologia, Departamento de Cirurgia Clínica e Patologia, Belo Horizonte, MG https://orcid.org/0009-0004-3941-3248
Talita Roberta Ferreira de Souza Universidade Federal de Minas Gerais, Faculdade de Medicina, Belo Horizonte, MG https://orcid.org/0009-0006-3633-6915
Matheus Oliveira Reis Universidade Federal de Minas Gerais, Faculdade de Medicina, Belo Horizonte, MG https://orcid.org/0009-0002-8197-5493
Felipe Morando Avelar Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Departamento de Genética, Ecologia e Evolução, Belo Horizonte, MG https://orcid.org/0000-0002-1744-448X
Maria Raquel Santos Carvalho Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Departamento de Genética, Ecologia e Evolução, Belo Horizonte, MG https://orcid.org/0000-0002-1744-448X
Vasco Ariston Carvalho de Azevedo Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Departamento de Genética, Ecologia e Evolução, Belo Horizonte, MG https://orcid.org/0000-0002-2557-7768
Debmalya Barh Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Departamento de Genética, Ecologia e Evolução, Belo Horizonte, MG https://orcid.org/0000-0002-2557-7768

DOI:

https://doi.org/10.1590/1678-7757-2024-0489

Keywords:

Amelogenesis Imperfecta, Enamel, Tooth, Gene, ENAM

Abstract

Amelogenesis imperfecta (AI) encompasses a group of conditions characterized by abnormalities in the development or function of tooth enamel. Clinical manifestations include different forms and degrees of enamel frailty, associated with sensitivity, tooth fractures, stains, abnormal tooth morphology, missing teeth, etc. AI is genetically heterogeneous, with over 70 genes associated with autosomal dominant, autosomal recessive, X-linked, and oligogenic inheritance. Objective To identify genetic variants associated with AI in a single family. Methodology We describe the clinical findings of a family affected by AI, composed of five individuals: four affected (the father and three daughters) and one unaffected (the mother). The observed segregation pattern suggests a dominant, X-linked inheritance. Genetic variants were screened using whole-exome sequencing. The initial bioinformatic analysis was conducted using Qiagen QCI, and variants were selected based on their presence in all four affected family members and absence in the unaffected mother. Search terms included “amelogenesis imperfecta,” “tooth,” and “enamel.” Several types of software were used to classify variants according to pathogenicity. Results Candidate variants were identified 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 pathogenic or likely pathogenic in AI. Discussion Among the identified genes, only ENAM has previously been associated with AI; however, IFIH1, PRICKLE3, and GPC3 are associated with dental/enamel development. The relatively high number of candidate genes and 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 same variants, AI-affected family members show considerable phenotypic variant, suggesting the involvement of non-shared genetic or environmental factors.

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

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