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I. Tsui, J. Tosi, J. Zernant, E. Haamer, C. Chou, I. Corcostegui, S. Tsang, R. Allikmets; Novel Mutations and Phenotypes in Phosphodiesterase 6 Deficiency. Invest. Ophthalmol. Vis. Sci. 2008;49(13):145.
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© ARVO (1962-2015); The Authors (2016-present)
Identifying the genetic defect in individuals affected with autosomal recessive retinitis pigmentosa (arRP) remains a challenging task due to substantial genetic heterogeneity and because variants in at least 17 genes have been associated with arRP. Identifying the causal gene is necessary for disease prognosis and for implementing emerging therapeutic options. The purpose of our work is to apply high throughput mutation and polymorphism detection (or screening techniques) for clinical diagnosis and counseling in families with retinitis pigmentosa.
We screened a cohort of 40 unrelated RP patients with a recently introduced arRP microarray, which contains >500 mutations from all 17 genes associated with arRP. One family with PDE6A retinitis pigmentosa underwent pedigree analysis, direct sequencing, and segregation analysis to find the precise genetic defect. Patients with PDE6 deficiencies were also phenotyped with optical coherence tomography, autofluorescence, and microperimetry.
A disease-associated allele was identified in 33% of patients. Two probands (5%) had PDE6 defects. The first proband, who was a compound heterozygote for known R102C and N216S alleles in the gene encoding PDE6A (MIM#180071), had 2 affected and several unaffected siblings available for segregation analysis. Pedigree analysis determined that the N216S variant is benign and direct sequencing discovered a novel, S303C, allele which, together with R102C, segregated with the disease. The second proband, of no relation to the previous kindred, had a homozygous D600N mutation in the PDE6B gene (MIM#180072). Visual acuities of these four PDE6 patients ranged from 20/40 to 20/200. Electroretinography (ERG) revealed generalized rod-cone photoreceptor dysfunction and intraretinal pigment migration along retinal arterioles were seen in all patients. Although PDE6 has photoreceptor-specific expression, one patient showed extensive vitreomacular traction that phenocopied Goldman-Favre syndrome.
This case series demonstrate that a combination of high throughput DNA microarray screening and advanced clinical methods are essential in the efficient workup of inherited diseases with high genetic heterogeneity. Precise molecular diagnosis and carrier detection is important to warn heterozygous carriers of PDE6 mutations about the risk of losing vision when using drugs such as sildenafil, taladafil, or vardenafil.
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