A Novel Mutation in PITX2 in a Patient with Axenfeld-Rieger Syndrome

Axenfeld-Rieger syndrome is a rare autosomal dominant condition. Anomalies include anterior segment dysgenesis of the eye, dental anomalies, maxillary hypoplasia, periumbilical anomalies, and congenital heart defects. We report a patient with Peters anomaly, dysmorphic features, congenital heart defect, umbilical hernia, short stature, and developmental delay. Diagnostic sequencing of 23 genes known to be causally related to the condition was performed on the patient, parents, and maternal grandparents. A variant of uncertain significance in PITX2 was identified. The mother had the same mutation and the father did not. The mother had decreased vision, congenitally missing teeth, and required jaw surgery as a child. Her asymptomatic parents elected to be tested and were negative for the mutation. The mutation, NM_153427.2:c.272G>A (p.Arg91Gln), is predicted to be damaging by PolyPhen-2 (score of 0.997), identified as a missense mutation with an allele frequency of 1.648e-05 by the Exome Aggregation Consortium, and has been reported in ClinVar once, by the laboratory that analyzed our patient's sample. Due to the in silico predictions and the results of family studies, it is suggested that this variant can be classified as pathogenic according to the American College of Medical Genetics and Genomics 2015 rule Pathogenic(iii)(b), specifically rules PS2, PM2, PM5, PP1, and PP3.