Dataset Information

A Chinese family with Axenfeld-Rieger syndrome: report of the clinical and genetic findings.

ABSTRACT: AIM:To describe a Chinese family affected by a severe form of Axenfeld-Rieger syndrome (ARS) and characterize the molecular defect in PITX2 in the family. METHODS:Patients presented with typical ARS from a Chinese family were investigated. We performed genome-wide linkage scan and exome sequencing to identify the pathogenic mutations. Candidate mutations were verified for co-segregation in the whole pedigree using Sanger sequencing. Real-time polymerase chain reaction (RT-PCR) and Western blotting were performed to verify the expression of the pathogenic gene. RESULTS:Genome-wide linkage and exome sequencing analyses showed PITX2 as the disease candidate gene. A>G substitution at position -11 of 3'ss of exon 5 (IVS5-11A>G) that co-segregated with the disease phenotype was discovered in the family. The PITX2 messenger ribonucleic acid and protein levels were about 50% lower in patients with ARS than in unaffected family members in the family. CONCLUSION:Our findings implicate the first intronic mutation of the PITX2 gene in the pathogenesis of a severe form of ARS in a Chinese family. This study highlights the importance of a systematic search for intronic mutation in ARS cases for which no mutations in the exons of PITX2 have been found.

SUBMITTER: Sun DP

PROVIDER: S-EPMC5515146 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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A Chinese family with Axenfeld-Rieger syndrome: report of the clinical and genetic findings.

Sun Da-Peng DP Dai Yun-Hai YH Pan Xiao-Jing XJ Shan Tao T Wang Dian-Qiang DQ Chen Peng P

International journal of ophthalmology 20170618 6

<h4>Aim</h4>To describe a Chinese family affected by a severe form of Axenfeld-Rieger syndrome (ARS) and characterize the molecular defect in <i>PITX2</i> in the family.<h4>Methods</h4>Patients presented with typical ARS from a Chinese family were investigated. We performed genome-wide linkage scan and exome sequencing to identify the pathogenic mutations. Candidate mutations were verified for co-segregation in the whole pedigree using Sanger sequencing. Real-time polymerase chain reaction (RT-P ...[more]

PMID: 28730073

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Project description:Purpose:To identify the genetic cause in a four-generation Chinese family with Axenfeld-Rieger syndrome (ARS). Methods:The family members received clinical examinations of the eye, tooth, periumbilical skin, and heart. Sanger sequencing and whole-exome sequencing (WES) were performed to screen potential mutations. The genomic deletion region around the PITX2 gene was estimated from single nucleotide polymorphism (SNP) data from WES and then confirmed with "quantitative PCR (qPCR) using a set of primers. The DNA breakpoint was further identified with long-range PCR and Sanger sequencing. Results:Symptoms including anterior segment dysplasia of the eye (iris dysplasia, multiple pupils, and posterior embryotoxon), dental dysplasia, and periumbilical skin redundancy were present in all of the affected individuals. Three of them had glaucoma. Corneal abnormalities (inferior sclerocornea, corneal endothelial dystrophy, and central corneal scar) were seen in most of the affected individuals. Cataract, limited eye movement, electrocardiographic abnormalities, intellectual disability, and recurrent miscarriages were observed in some of the affected individuals. No mutations in the coding and exon-intron adjacent regions of the PITX2 and FOXC1 genes were identified with Sanger sequencing. According to the SNP data from WES, we suspected that there might be a deletion region (at most 1.6 Mb) around the PITX2 gene. With the use of qPCR and long-range PCR, we identified a 53,840 bp deletion (chr4: 111,535,454-111,588,933) spanning PITX2 and PANCR. The genomic deletion cosegregated with the major ARS symptoms observed in the family members. Conclusions:With the help of WES, qPCR, and long-range PCR, we identified a genomic deletion encompassing PITX2 and the adjacent noncoding gene PANCR in a Chinese family with ARS. The clinical features of the affected individuals are reported. This work may broaden understanding of the phenotypic and mutational spectrums related to ARS.

Dataset Information

A Chinese family with Axenfeld-Rieger syndrome: report of the clinical and genetic findings.

Publications

A Chinese family with Axenfeld-Rieger syndrome: report of the clinical and genetic findings.

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