Reduced penetrance in a large Caucasian pedigree with Stickler syndrome

<i>Background</i>: 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 <i>COL2A1</i> or <i>VCAN</i>. We utilized linkage mapping and exome sequencing to identify the causal variant. <i>Materials and methods</i>: 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. <i>Results</i>: Parametric multipoint linkage analysis using an AD inheritance model demonstrated HLOD scores &gt; 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 &gt; 1.0. Exome sequencing revealed a novel nonsense mutation (c.115C&gt;T, p.Gln39*) in exon 2 of <i>COL2A1</i> 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. <i>Conclusions</i>: 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 <i>COL2A1</i> 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 <i>COL2A1</i> that displays incomplete penetrance and/or variable age of onset with extraocular manifestations.