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Kaylie Webb-Jones, Sara J Bowne, Lori S Sullivan, Stephen P Daiger, Feng Wang, Rui Chen, David G Birch, Dianna K H Wheaton; Identification of mutations in three retinal dystrophy genes within a single family: PRPF8, PRPH2 and USH2A. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2887. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To describe clinical and molecular characteristics of a family with seemingly incomplete penetrant, autosomal dominant retinitis pigmentosa (RP).
Two female first cousins (20 & 22 yrs), previously diagnosed with RP with no reported hearing loss, and their respective mothers (48 & 53 yrs) underwent visual function exam and genotyping performed by capture next generation sequencing (NGS; 163 genes) and/or Sanger sequencing. Familial relationships were confirmed with short tandem repeat (STR) markers.
The proband (#8438) had VA=20/25 OU, Humphrey visual fields (HVF) were borderline reduced-to-mildly constricted, ffERG rod responses were reduced 88% in amplitude and delayed, cone 30Hz flicker responses were reduced 76% and delayed, OCT imaging showed photoreceptor layer limited to the fovea and para-fovea, no bone-spicule pigment was visible on fundus photography. Genetic analysis identified two known USH2A mutations in trans: p.Glu767Serfs*21 and p.Glu3448Lys. The proband’s mother (#9959) carries the USH2A p.Glu767Serfs*21 mutation and is asymptomatic with a normal appearing retina on OCT.<br /> <br /> The proband’s first cousin (#10228) had VA=20/32 OD, 20/40 OS, HVF constricted to <30°, ffERG rod responses were reduced 87% and delayed , cone 30Hz flicker responses were reduced 89% and delayed, imaging indicated photoreceptor layer limited to the fovea and para-fovea, and moderate bone-spicule pigment. Heterozygous mutations in three different retinal degeneration genes were identified in #10228 using NGS: PRPH2 p.Tyr204Arg and USH2A p.Glu767Serfs*21, and a novel, likely pathogenic mutation, p.Thr1931Met in PRPF8. Her mother (#10524) had VA=20/200 OD, 20/400 OS, ffERG rod responses were non-detectable, cone 30Hz flicker responses were reduced 99% and normal in b-wave implicit time. OCT scans showed thinning of the retina with only remnants of the photoreceptor layer remaining in the fovea, dense mid-periphery bone-spicule pigment was observed; heterozygous PRPF8 and USH2A p.Glu767Serfs*21 mutations were identified.
Genotyping of families has classically taken into account only one gene being responsible for the disease phenotype, particularly in families of small relative size. Using NGS methods, mutations were identified in three retinal dystrophy genes contributing to both dominant (PRPF8, PRPH2) and recessive RP (USH2A) within one family.
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