Whole exome sequencing identifies a heterozygous missense variant in the PRDM5 gene in a family with Axenfeld-Rieger syndrome

Abstract

Axenfeld-Rieger syndrome (ARS) is a disorder affecting the anterior segment of the eye, often leading to secondary glaucoma and several systemic malformations. It is inherited in an autosomal dominant fashion that has been associated with genetic defects in PITX2 and FOXC1. Known genes CYP1b1, PITX2, and FOXC1 were excluded by Sanger sequencing. The purpose of current study is to identify the underlying genetic causes in ARS family by whole exome sequencing (WES). WES was performed for affected proband of family, and variants were prioritized based on in silico analyses. Segregation analysis of candidate variants was performed in family members. A novel heterozygous PRDM5 missense variant (c.877A>G; p.Lys293Glu) was found to segregate with the disease in an autosomal dominant fashion. The novel missense variant was absent from population-matched controls, the Exome Variant Server, and an in-house exome variant database. The Lys293Glu variant is predicted to be pathogenic and affects a lysine residue that is conserved in different species. Variants in the PRDM5 gene were previously identified in anterior segment defects, i.e., autosomal recessive brittle cornea syndrome and keratoconus. The results of this study suggest that genetic variants in PRDM5 can lead to various syndromic and nonsyndromic disorders affecting the anterior segment of the eye.

Keywords: Axenfeld–Rieger syndrome; PRDM5; Whole exome sequencing.

Fig. 1

Segregation of a PRDM5 missense variant in a family with Axenfeld–Rieger syndrome. The c.877A>G; p.Lys293Glu variant is indicated with an M, and the wild-type allele with a +. All affected individuals carry the variant heterozygously, while the unaffected individuals do not carry the variant. The proband is indicated with an arrow

Fig. 2

Ocular and systemic characteristics of the family with Axenfeld–Rieger syndrome. a Eyes of the proband (VI:3) presented bilateral buphthalmos, corectopia, polycoria, corneal edema, posterior embryotoxon, posterior subcapsular cataract, vascularized corneal opacity, and iris atropy patches in the left eye. b Both eyes of individual (VI:5) showed megalocornea and posterior embryotoxon. The right eye shows polycoria, and the left eye shows corectopia. c Facial dysmorphism in individuals VI:3 included flattening of the mid-face, a broad forehead, a broad nasal bridge, a thin upper lip with a long philtrum, a protruding lower lip, and a receding chin; d microdontia; e micrognathia; f redundant periumbilical skin

Fig. 3

PRDM5 protein sequence alignment (amino acids 283–303) across species, indicating evolutionary conservation of lysine at position 293 in human PRDM5

Fig. 4

Secondary structure of the PRDM5 protein. The Lys residue in the linker region between two Zn-finger domains is represented with the green color, and the mutant Glu variant is indicated with a red color