Reduced penetrance in a large Caucasian pedigree with Stickler syndrome.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Tompson, SW; Johnson, C; Abbott, D; Bakall, B; Soler, V; Yanovitch, TL; Whisenhunt, KN; Klemm, T; Rozen, S; Stone, EM; Johnson, M; Young, TL

Published Date

  • January 2017

Published In

Volume / Issue

  • 38 / 1

Start / End Page

  • 43 - 50

PubMed ID

  • 28095098

Pubmed Central ID

  • PMC6680000

Electronic International Standard Serial Number (EISSN)

  • 1744-5094

Digital Object Identifier (DOI)

  • 10.1080/13816810.2016.1275018


  • eng

Conference Location

  • England