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Whole exome sequencing identifies a heterozygous missense variant in the PRDM5 gene in a family with Axenfeld-Rieger syndrome.
Neurogenetics. 2016 Jan; 17(1):17-23.N

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.

Authors+Show Affiliations

Department of Ophthalmology, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. Shazia.Micheal@radboudumc.nl.Department of Pediatric Ophthalmology, Al-Shifa Eye Trust Hospital Jhelum Road, Rawalpindi, Pakistan.Department of Pediatric Ophthalmology, Al-Shifa Eye Trust Hospital Jhelum Road, Rawalpindi, Pakistan.Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan. Al-Nafees Medical College and Hospital, Isra University, Islamabad, Pakistan.Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.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.

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26489929

Citation

Micheal, Shazia, et al. "Whole Exome Sequencing Identifies a Heterozygous Missense Variant in the PRDM5 Gene in a Family With Axenfeld-Rieger Syndrome." Neurogenetics, vol. 17, no. 1, 2016, pp. 17-23.
Micheal S, Siddiqui SN, Zafar SN, et al. Whole exome sequencing identifies a heterozygous missense variant in the PRDM5 gene in a family with Axenfeld-Rieger syndrome. Neurogenetics. 2016;17(1):17-23.
Micheal, S., Siddiqui, S. N., Zafar, S. N., Venselaar, H., Qamar, R., Khan, M. I., & den Hollander, A. I. (2016). Whole exome sequencing identifies a heterozygous missense variant in the PRDM5 gene in a family with Axenfeld-Rieger syndrome. Neurogenetics, 17(1), 17-23. https://doi.org/10.1007/s10048-015-0462-0
Micheal S, et al. Whole Exome Sequencing Identifies a Heterozygous Missense Variant in the PRDM5 Gene in a Family With Axenfeld-Rieger Syndrome. Neurogenetics. 2016;17(1):17-23. PubMed PMID: 26489929.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Whole exome sequencing identifies a heterozygous missense variant in the PRDM5 gene in a family with Axenfeld-Rieger syndrome. AU - Micheal,Shazia, AU - Siddiqui,Sorath Noorani, AU - Zafar,Saemah Nuzhat, AU - Venselaar,Hanka, AU - Qamar,Raheel, AU - Khan,Muhammad Imran, AU - den Hollander,Anneke I, Y1 - 2015/10/21/ PY - 2015/07/14/received PY - 2015/09/20/accepted PY - 2015/10/23/entrez PY - 2015/10/23/pubmed PY - 2016/11/12/medline KW - Axenfeld–Rieger syndrome KW - PRDM5 KW - Whole exome sequencing SP - 17 EP - 23 JF - Neurogenetics JO - Neurogenetics VL - 17 IS - 1 N2 - 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. SN - 1364-6753 UR - https://www.unboundmedicine.com/medline/citation/26489929/Whole_exome_sequencing_identifies_a_heterozygous_missense_variant_in_the_PRDM5_gene_in_a_family_with_Axenfeld_Rieger_syndrome_ L2 - https://dx.doi.org/10.1007/s10048-015-0462-0 DB - PRIME DP - Unbound Medicine ER -