Whole exome sequencing identifies a heterozygous missense variant in the PRDM5 gene in a family with Axenfeld-Rieger syndrome.
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.
Department of Ophthalmology, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. Shazia.Micheal@radboudumc.nl.
Shazia
S
Micheal
Department of Pediatric Ophthalmology, Al-Shifa Eye Trust Hospital Jhelum Road, Rawalpindi, Pakistan.
Sorath Noorani
SN
Siddiqui
Department of Pediatric Ophthalmology, Al-Shifa Eye Trust Hospital Jhelum Road, Rawalpindi, Pakistan.
Saemah Nuzhat
SN
Zafar
Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Hanka
H
Venselaar
Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.|Al-Nafees Medical College and Hospital, Isra University, Islamabad, Pakistan.
Raheel
R
Qamar
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Muhammad Imran
MI
Khan
Department of Ophthalmology, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. Anneke.denHollander@radboudumc.nl.|Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. Anneke.denHollander@radboudumc.nl.
Anneke I
AI
den Hollander
D000869:Anterior Eye Segment / Q000002:abnormalities*; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome; D005124:Eye Abnormalities / Q000235:genetics*; D015785:Eye Diseases, Hereditary; D005190:Family; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
D004268:DNA-Binding Proteins; C487762:PRDM5 protein, human; D014157:Transcription Factors
Axenfeld–Rieger syndrome; PRDM5; Whole exome sequencing