June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Autosomal dominant locus for pediatric cataract, myopic astigmatism, familial exudative vitreoretinopathy and primary open-angle glaucoma identified on chromosome 7q36
Author Affiliations & Notes
  • Stuart W Tompson
    Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States
  • Kristina N Whisenhunt
    Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States
  • Alex W Hewitt
    Centre for Eye Research Australia, University of Melbourne, Melbourne, Victoria, Australia
    Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
  • David A Mackey
    Centre for Eye Research Australia, University of Melbourne, Melbourne, Victoria, Australia
    Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
  • Terri L Young
    Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States
  • Footnotes
    Commercial Relationships   Stuart Tompson, None; Kristina Whisenhunt, None; Alex Hewitt, None; David Mackey, None; Terri Young, None
  • Footnotes
    Support  NIH/NEI RO1 EY014685, Research to Prevent Blindness, Inc., University of Wisconsin Centennial Scholar Award
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 2787. doi:
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      Stuart W Tompson, Kristina N Whisenhunt, Alex W Hewitt, David A Mackey, Terri L Young; Autosomal dominant locus for pediatric cataract, myopic astigmatism, familial exudative vitreoretinopathy and primary open-angle glaucoma identified on chromosome 7q36. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2787.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : In a large multi-generational Australian pedigree (European descent) presenting with an autosomal dominant constellation of pediatric cataract, myopic astigmatism, familial exudative vitreoretinopathy and primary open-angle glaucoma phenotypes, we performed linkage analysis and exome sequencing to map and identify the genetic cause.

Methods : SNP genotyping was performed on 12 affected and 4 unaffected individuals using HumanOmniExpress-24 BeadChips. From an initial 713K genotyped SNPs, GenomeStudio software was used to select the highest quality 103K SNPs, which were used as input for Superlink-Online SNP linkage analysis. Multi-point linkage analysis and haplotyping were performed by Superlink on a random subset of approximately 1,000 markers on each chromosome (23,359 SNPs total), generating LOD scores across the genome via a hidden Markov model algorithm. The mode of inheritance was set as dominant with 0.99 penetrance. Exome sequencing was performed on 4 affected individuals using a Roche Nimblegen SeqCap EZ Exome V3 capture kit and 100bp paired-end reads on an Illumina HiSeq2000 platform. Sequence reads were aligned to the hg19 reference genome with BWA, variants called with GATK, and analysis performed using Golden Helix SVS software.

Results : Multi-point linkage analysis identified a single 7.46mb region located at the telomeric end of chromosome 7q36 with a maximum LOD score of 3.3. Haplotype analysis confirmed co-segregation of a single haplotype in only the 12 affected individuals. A recombination event at rs9648731 delimited the centromeric end of the interval, which contained 43 genes. Exome sequencing of 4 affected individuals identified a single shared rare variant, c.1788C>T (p.C596C) in GALNT11. The synonymous variant has an allele frequency of 0.00003 in the ExAC database, and is predicted to destroy an SRSF1 (serine and arginine rich splicing factor 1) exonic splicing enhancer. In-house microarray expression data showed high GALNT11 expression in fetal retina/RPE, choroid, sclera, optic nerve, cornea, and adult retina and RPE.

Conclusions : We have identified a 7.46mb region containing 43 genes on chromosome 7q36 as a disease locus for this rare constellation of ocular phenotypes. Exome sequencing identified a single rare variant in GALNT11 that may affect splicing of the galactosyltransferase transcripts.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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