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Reduced penetrance in a large Caucasian pedigree with Stickler syndrome.

Publication ,  Journal Article
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 in: Ophthalmic Genet
2017

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.

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Published In

Ophthalmic Genet

DOI

EISSN

1744-5094

Publication Date

2017

Volume

38

Issue

1

Start / End Page

43 / 50

Location

England

Related Subject Headings

  • White People
  • Retinal Detachment
  • Polymerase Chain Reaction
  • Penetrance
  • Pedigree
  • Ophthalmology & Optometry
  • Middle Aged
  • Male
  • Humans
  • Hearing Loss, Sensorineural
 

Citation

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Tompson, S. W., Johnson, C., Abbott, D., Bakall, B., Soler, V., Yanovitch, T. L., … Young, T. L. (2017). Reduced penetrance in a large Caucasian pedigree with Stickler syndrome. Ophthalmic Genet, 38(1), 43–50. https://doi.org/10.1080/13816810.2016.1275018
Tompson, Stuart W., Charles Johnson, Diana Abbott, Benjamin Bakall, Vincent Soler, Tammy L. Yanovitch, Kristina N. Whisenhunt, et al. “Reduced penetrance in a large Caucasian pedigree with Stickler syndrome.Ophthalmic Genet 38, no. 1 (2017): 43–50. https://doi.org/10.1080/13816810.2016.1275018.
Tompson SW, Johnson C, Abbott D, Bakall B, Soler V, Yanovitch TL, et al. Reduced penetrance in a large Caucasian pedigree with Stickler syndrome. Ophthalmic Genet. 2017;38(1):43–50.
Tompson, Stuart W., et al. “Reduced penetrance in a large Caucasian pedigree with Stickler syndrome.Ophthalmic Genet, vol. 38, no. 1, 2017, pp. 43–50. Pubmed, doi:10.1080/13816810.2016.1275018.
Tompson SW, Johnson C, Abbott D, Bakall B, Soler V, Yanovitch TL, Whisenhunt KN, Klemm T, Rozen S, Stone EM, Johnson M, Young TL. Reduced penetrance in a large Caucasian pedigree with Stickler syndrome. Ophthalmic Genet. 2017;38(1):43–50.

Published In

Ophthalmic Genet

DOI

EISSN

1744-5094

Publication Date

2017

Volume

38

Issue

1

Start / End Page

43 / 50

Location

England

Related Subject Headings

  • White People
  • Retinal Detachment
  • Polymerase Chain Reaction
  • Penetrance
  • Pedigree
  • Ophthalmology & Optometry
  • Middle Aged
  • Male
  • Humans
  • Hearing Loss, Sensorineural