Reduced penetrance in a large Caucasian pedigree with Stickler syndrome. (2nd January 2017)

• Record Type: Journal Article
• Authors: Tompson, Stuart W.; Johnson, Charles; Abbott, Diana; Bakall, Benjamin; Soler, Vincent; Yanovitch, Tammy L.; Whisenhunt, Kristina N.; Klemm, Thomas; Rozen, Steve; Stone, Edwin M.; Johnson, Max; Young, Terri L.
• Is Part Of: Ophthalmic genetics. Volume 38:Number 1(2017)
• Page Start: 43
• Page End: 50
• Publication Date: 2017-01-02
• Subjects: Linkage -- penetrance -- Stickler syndrome -- Wagner syndrome; Eye -- Diseases -- Genetic aspects -- Periodicals; Eye Diseases -- genetics -- Periodicals; Eye Diseases -- in infancy & childhood -- Periodicals; 617.7
• DOI: 10.1080/13816810.2016.1275018
• Languages: English
• ISSNs: 1381-6810

Abstract

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.