Reduced penetrance in a large Caucasian pedigree with Stickler syndrome

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.

KEYWORDS:

• Linkage
• penetrance
• Stickler syndrome
• Wagner syndrome

Supplemental data

Supplemental data for this article can be accessed on the publisher’s website.

Acknowledgments

The authors would like to thank all family members for participation in the study. We wish to also acknowledge the technical contributions of Caldwell Powell, Whitney Call, Valencia Quiett, and Erica Nading.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Funding

This research was funded by the National Institutes of Health Grant R01 EY014685, the Lew Wasserman Award from Research to Prevent Blindness Inc., New York, NY, an unrestricted departmental grant from Research to Prevent Blindness, Inc, New York, NY, and a Duke-National University of Singapore core grant to Terri Young. Vincent Soler was supported by the Toulouse Hospital Young Researcher Fellowship, the Fondation pour la Recherche Médicale, and Fondation de France. Benjamin Bakall is supported by a Foundation Fighting Blindness career development award.

Additional information

Funding

This research was funded by the National Institutes of Health Grant R01 EY014685, the Lew Wasserman Award from Research to Prevent Blindness Inc., New York, NY, an unrestricted departmental grant from Research to Prevent Blindness, Inc, New York, NY, and a Duke-National University of Singapore core grant to Terri Young. Vincent Soler was supported by the Toulouse Hospital Young Researcher Fellowship, the Fondation pour la Recherche Médicale, and Fondation de France. Benjamin Bakall is supported by a Foundation Fighting Blindness career development award.