Kamps Rick, Martens Herm, de Koning Bart, Smeets Bert, van Geel Michel
Department of Translational Genomics, Maastricht University, Maastricht, the Netherlands.
Department of Dermatology, Maastricht University Medical Centre+, Maastricht, the Netherlands.
Mol Genet Genomic Med. 2025 Jun;13(6):e70108. doi: 10.1002/mgg3.70108.
Amelogenesis imperfecta (AI) is a rare genetic disorder causing tooth enamel defects. AI has been classified into 14 different clinical subtypes with different modes of inheritance. In this study, we performed whole-exome sequencing to identify the causative gene defect in a large Dutch family with autosomal dominant hypocalcified AI (ADHCAI).
Whole-exome sequencing (WES) was performed on genomic DNA of the proband with AI. We focused on eight candidate genes known to be involved in inherited autosomal dominant AI. Sanger sequencing was used to confirm the selected exome candidate variant. Additionally, genotype and phenotype analyses were performed in the selected affected and non-affected individuals and compared according to previously listed literature for this candidate gene of the proband.
The clinical phenotype of the affected individuals showed a generalized and extensive enamel defect of all teeth. In the exome dataset of the proband, a novel nonsense variant in FAM83H, c.1055C>A p.(Ser352*) was detected, which was verified by conventional Sanger sequencing. Co-segregation analysis confirmed that the variant was present in all affected individuals and not in unaffected individuals.
A novel pathogenic, protein-truncating variant was detected in FAM83H, a gene with similar truncating variants known to be associated with ADHCAI.
牙釉质发育不全（AI）是一种导致牙釉质缺陷的罕见遗传性疾病。AI已被分为14种不同的临床亚型，具有不同的遗传模式。在本研究中，我们进行了全外显子组测序，以确定一个患有常染色体显性低钙化型牙釉质发育不全（ADHCAI）的荷兰大家庭中的致病基因缺陷。
对患有AI的先证者的基因组DNA进行全外显子组测序（WES）。我们聚焦于已知与遗传性常染色体显性AI相关的8个候选基因。使用桑格测序法确认所选外显子组候选变异。此外，对所选的受累和未受累个体进行基因型和表型分析，并根据先证者该候选基因的先前列出的文献进行比较。
受累个体的临床表型显示所有牙齿均存在广泛性和广泛性牙釉质缺陷。在先证者的外显子组数据集中，检测到FAM83H基因中的一个新的无义变异，c.1055C>A p.(Ser352*)，通过传统桑格测序法进行了验证。共分离分析证实该变异存在于所有受累个体中，而不存在于未受累个体中。
在FAM83H基因中检测到一个新的致病的、蛋白质截短变异，该基因具有已知与ADHCAI相关的类似截短变异。
