Journal article
Reduced penetrance in a large Caucasian pedigree with Stickler syndrome
Ophthalmic Genetics: Festschrift Honoring Irene Hussels Maumenee, Vol.38(1), pp.43-50
01/02/2017
DOI: 10.1080/13816810.2016.1275018
PMCID: PMC6680000
PMID: 28095098
Abstract
Background: In a four-generation Caucasian family variably diagnosed with autosomal dominant (AD) Stickler or Wagner disease, commercial gene screening failed to identify a mutation in COL2A1 or VCAN. We utilized linkage mapping and exome sequencing to identify the causal variant. Materials and methods: Genomic DNA samples collected from 40 family members were analyzed. A whole-genome linkage scan was performed using Illumina HumanLinkage-24 BeadChip followed by two-point and multipoint linkage analyses using FASTLINK and MERLIN. Exome sequencing was performed on two affected individuals, followed by co-segregation analysis. Results: Parametric multipoint linkage analysis using an AD inheritance model demonstrated HLOD scores > 2.00 at chromosomes 1p36.13-1p36.11 and 12q12-12q14.1. SIMWALK multipoint analysis replicated the peak in chromosome 12q (peak LOD = 1.975). FASTLINK two-point analysis highlighted several clustered chromosome 12q SNPs with HLOD > 1.0. Exome sequencing revealed a novel nonsense mutation (c.115C>T, p.Gln39*) in exon 2 of COL2A1 that is expected to result in nonsense-mediated decay of the RNA transcript. This mutation co-segregated with all clinically affected individuals and seven individuals who were clinically unaffected. Conclusions: The utility of combining traditional linkage mapping and exome sequencing is highlighted to identify gene mutations in large families displaying a Mendelian inheritance of disease. Historically, nonsense mutations in exon 2 of COL2A1 have been reported to cause a fully penetrant ocular-only Stickler phenotype with few or no systemic manifestations. We report a novel nonsense mutation in exon 2 of COL2A1 that displays incomplete penetrance and/or variable age of onset with extraocular manifestations.
Details
- Title: Subtitle
- Reduced penetrance in a large Caucasian pedigree with Stickler syndrome
- Creators
- Stuart W Tompson - Department of Ophthalmology and Visual Sciences, University of Wisconsin - MadisonCharles JohnsonDiana Abbott - Department of Biostatistics and Informatics, University of Colorado Anschutz Medical CampusBenjamin Bakall - Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of MedicineVincent Soler - Centre de Physiopathologie de Toulouse Purpan, Université Paul SabatierTammy L Yanovitch - Department of Ophthalmology, Dean McGee Eye Institute, University of OklahomaKristina N Whisenhunt - Department of Ophthalmology and Visual Sciences, University of Wisconsin - MadisonThomas Klemm - Duke-National University of Singapore Graduate Medical SchoolSteve Rozen - Duke-National University of Singapore Graduate Medical SchoolEdwin M Stone - Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of MedicineMax JohnsonTerri L Young - Duke-National University of Singapore Graduate Medical School
- Resource Type
- Journal article
- Publication Details
- Ophthalmic Genetics: Festschrift Honoring Irene Hussels Maumenee, Vol.38(1), pp.43-50
- DOI
- 10.1080/13816810.2016.1275018
- PMID
- 28095098
- PMCID
- PMC6680000
- NLM abbreviation
- Ophthalmic Genet
- ISSN
- 1381-6810
- eISSN
- 1744-5094
- Publisher
- Taylor & Francis
- Grant note
- Young Researcher Fellowship / Centre Hospitalier Universitaire de Toulouse N/A / Fondation de France N/A / Fondation pour la Recherche Médicale Core Grant / Duke-National University of Singapore R01 EY014685 / National Institutes of Health Career Development Award / Foundation Fighting Blindness Lew Wasserman Award / Research to Prevent Blindness
- Language
- English
- Date published
- 01/02/2017
- Academic Unit
- Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
- Record Identifier
- 9983979963002771
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