Identification of WDR72 Mutations in Families With Hypomaturation Amelogenesis Imperfecta

Objectives: Hypomaturation forms of autosomal recessive amelogenesis imperfecta (ARAI) can be manifested as isolated (non-syndromic) enamel malformations, as has so far been the case with biallelic mutations in WDR72, KLK4, GPR68 and SLC24A4. Hypomaturation forms of ARAI also occur in syndromic conditions, examples of which include Immunodeficiency 9 (ORAI1), Immunodeficiency 10 (STIM1), Heimler Syndrome (PEX1/PEX6) and Cone-Rod Dystrophy and AI (CNNM4). As the systemic phenotype of syndromic AI can be subtle and have a later onset than the dental phenotype, distinguishing isolated from syndromic forms of hypomaturation ARAI is often not possible clinically. Determining the genetic causality of hypomaturation AI in affected families can improve patient monitoring and management. Our objective was to identify the disease-causing mutations in families with hypomaturation ARAI.
Methods: ARAI families were analyzed by whole exome sequencing (WES) of genomic DNA from both parents and at least one affected offspring. Raw reads were aligned against human genome assembly GRCh37 using BWA. Variants were called and calibrated using GATK. High confidence variants were annotated and filtered by VarSeq. Potentially damaging mutations were prioritized and screened for each family. Sanger sequencing was performed with all available samples in each family to validate cosegregation of phenotype and genotype.
Results: We identified homozygous (biallelic) WDR72 mutations (in exons 5, 11, and 12) in three unrelated Turkish families (NM_182758.2: c.377G>A, p.Trp126*; c.1265G>T, p.Gly422Val; c.1467_1468delAT, p.Val491fs*8). These mutations showed either a minor allele frequency (MAF) value lower than 0.008% or had not yet determined (missing). Sanger sequencing was performed on all participating members of these families and demonstrated perfect cosegregation of the biallelic WDR72 mutations with the AI phenotype.
Conclusions: We identified novel ARAI-causing WDR72 mutations. Despite the varied positions of the mutations in the WDR72 gene, the clinical presentation was consistent among all affected persons.