title: Reduced penetrance in a large Caucasian pedigree with Stickler syndrome.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: a Department of Ophthalmology and Visual Sciences , University of Wisconsin - Madison , Madison , Wisconsin , USA.
authors.forename: Stuart W
authors.initials: SW
authors.lastname: Tompson
authors.affiliation: b Retina Consultants, Ltd ., Fargo , North Dakota , USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Johnson
authors.affiliation: c Department of Biostatistics and Informatics , University of Colorado Anschutz Medical Campus , Aurora , Colorado , USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Abbott
authors.affiliation: d Department of Ophthalmology and Visual Sciences , University of Iowa Carver College of Medicine , Iowa City , Iowa , USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bakall
authors.affiliation: e Centre de Physiopathologie de Toulouse Purpan , Université Paul Sabatier , Toulouse , France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Soler
authors.affiliation: f Department of Ophthalmology, Dean McGee Eye Institute , University of Oklahoma , Oklahoma City , Oklahoma , USA.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Yanovitch
authors.affiliation: a Department of Ophthalmology and Visual Sciences , University of Wisconsin - Madison , Madison , Wisconsin , USA.
authors.forename: Kristina N
authors.initials: KN
authors.lastname: Whisenhunt
authors.affiliation: g Duke-National University of Singapore Graduate Medical School , Singapore.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klemm
authors.affiliation: g Duke-National University of Singapore Graduate Medical School , Singapore.
authors.forename: Steve
authors.initials: S
authors.lastname: Rozen
authors.affiliation: d Department of Ophthalmology and Visual Sciences , University of Iowa Carver College of Medicine , Iowa City , Iowa , USA.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.affiliation: b Retina Consultants, Ltd ., Fargo , North Dakota , USA.
authors.forename: Max
authors.initials: M
authors.lastname: Johnson
authors.affiliation: a Department of Ophthalmology and Visual Sciences , University of Wisconsin - Madison , Madison , Wisconsin , USA.|g Duke-National University of Singapore Graduate Medical School , Singapore.
authors.forename: Terri L
authors.initials: TL
authors.lastname: Young
mesh_terms: D000328:Adult; D000368:Aged; D001168:Arthritis / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D002874:Chromosome Mapping; D018389:Codon, Nonsense; D024043:Collagen Type II / Q000235:genetics*; D003240:Connective Tissue Diseases / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D005820:Genetic Testing; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D019683:Penetrance; D016133:Polymerase Chain Reaction; D012163:Retinal Detachment / Q000175:diagnosis / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: C499177:COL2A1 protein, human; D018389:Codon, Nonsense; D024043:Collagen Type II
keywords: Linkage; Stickler syndrome; Wagner syndrome; penetrance