Deletion of exon 4 of the PITX2 in a child with Axenfeld-Rieger syndrome.

Background: Axenfeld-Rieger syndrome (ARS, OMIM:602482) is a genetic disease characterized by ocular and systemic features. Clinical features of ARS are highly variable among patients and associated with mutations of human PITX2 and FOXC1 genes. Herein, we present an ARS in two cases (proband and his mother) with a novel variant in the PITX2.

Methods: A 3-month-old boy was admitted with an abnormal eye development at birth. Physical examination and ophthalmologic examination findings revealed an abnormal development of the anterior segments, ectropion of redundant skin in the umbilicus, single-sided deafness, teeth eruption failure, patent foramen ovale, and a mid-facial flattening. The proband's mother has been blind since the age of 12. We conducted genetic tests for the family via whole exome sequencing (WES) and quantitative PCR (qPCR) to identify the genetic etiology in the family. We also conducted a retrospective review of the ARS type I phenotype caused by the PITX2 mutations.

Results: WES and qPCR results of the proband and his parents suggested that both the child and his mother carry a 1.31kbp deletion (chr4: g.111538559_111539864del [GRCh37]) spanned the exon 4 of PITX2, resulting in the typical and rare phenotype of ARS type I. It can conclude that truncating variants in the exon 3-4 of PITX2 are the more common mechanism to cause the malfunction of the gene with a broader phenotypic spectrum.

Conclusion: The study has filled in a new clinical manifestation of the PITX2 and enriched the phenotype of ARS. The retrospective analysis of phenotype of PITX2 mutations provided a comprehensive understanding of the disease.