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Reduced penetrance in a large Caucasian pedigree with Stickler syndrome.
Ophthalmic Genet. 2017 Jan-Feb; 38(1):43-50.OG

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.

Authors+Show Affiliations

a Department of Ophthalmology and Visual Sciences , University of Wisconsin - Madison , Madison , Wisconsin , USA.b Retina Consultants, Ltd ., Fargo , North Dakota , USA.c Department of Biostatistics and Informatics , University of Colorado Anschutz Medical Campus , Aurora , Colorado , USA.d Department of Ophthalmology and Visual Sciences , University of Iowa Carver College of Medicine , Iowa City , Iowa , USA.e Centre de Physiopathologie de Toulouse Purpan , Université Paul Sabatier , Toulouse , France.f Department of Ophthalmology, Dean McGee Eye Institute , University of Oklahoma , Oklahoma City , Oklahoma , USA.a Department of Ophthalmology and Visual Sciences , University of Wisconsin - Madison , Madison , Wisconsin , USA.g Duke-National University of Singapore Graduate Medical School , Singapore.g Duke-National University of Singapore Graduate Medical School , Singapore.d Department of Ophthalmology and Visual Sciences , University of Iowa Carver College of Medicine , Iowa City , Iowa , USA.b Retina Consultants, Ltd ., Fargo , North Dakota , USA.a Department of Ophthalmology and Visual Sciences , University of Wisconsin - Madison , Madison , Wisconsin , USA. g Duke-National University of Singapore Graduate Medical School , Singapore.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28095098

Citation

Tompson, Stuart W., et al. "Reduced Penetrance in a Large Caucasian Pedigree With Stickler Syndrome." Ophthalmic Genetics, vol. 38, no. 1, 2017, pp. 43-50.
Tompson SW, Johnson C, Abbott D, et al. Reduced penetrance in a large Caucasian pedigree with Stickler syndrome. Ophthalmic Genet. 2017;38(1):43-50.
Tompson, S. W., Johnson, C., Abbott, D., Bakall, B., Soler, V., Yanovitch, T. L., Whisenhunt, K. N., Klemm, T., Rozen, S., Stone, E. M., Johnson, M., & Young, T. L. (2017). Reduced penetrance in a large Caucasian pedigree with Stickler syndrome. Ophthalmic Genetics, 38(1), 43-50. https://doi.org/10.1080/13816810.2016.1275018
Tompson SW, et al. Reduced Penetrance in a Large Caucasian Pedigree With Stickler Syndrome. Ophthalmic Genet. 2017 Jan-Feb;38(1):43-50. PubMed PMID: 28095098.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reduced penetrance in a large Caucasian pedigree with Stickler syndrome. AU - Tompson,Stuart W, AU - Johnson,Charles, AU - Abbott,Diana, AU - Bakall,Benjamin, AU - Soler,Vincent, AU - Yanovitch,Tammy L, AU - Whisenhunt,Kristina N, AU - Klemm,Thomas, AU - Rozen,Steve, AU - Stone,Edwin M, AU - Johnson,Max, AU - Young,Terri L, Y1 - 2017/01/17/ PY - 2017/1/18/pubmed PY - 2017/11/14/medline PY - 2017/1/18/entrez KW - Linkage KW - Stickler syndrome KW - Wagner syndrome KW - penetrance SP - 43 EP - 50 JF - Ophthalmic genetics JO - Ophthalmic Genet VL - 38 IS - 1 N2 - 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. SN - 1744-5094 UR - https://www.unboundmedicine.com/medline/citation/28095098/Reduced_penetrance_in_a_large_Caucasian_pedigree_with_Stickler_syndrome_ L2 - https://www.tandfonline.com/doi/full/10.1080/13816810.2016.1275018 DB - PRIME DP - Unbound Medicine ER -