Clinical findings of end-stage retinitis pigmentosa with a homozygous PDE6A variant (p.R653X)

Abstract

PurposeTo report clinical and genetic features of a Japanese patient with end-stage retinitis pigmentosa (RP) caused by a homozygous PDE6A variant.MethodsWe performed comprehensive ophthalmic examinations. Whole exome sequencing analysis was used to investigate the RP patient with parental consanguinity. The pedigree included 4 RP patients in the two generations, which suggests presumed pseudo-autosomal dominant inheritance.ResultsA PDE6A variant (p.R653X) was identified to be homozygous and disease-causing in the patient. Homozygosity mapping revealed the homozygous region including the variant and confirmation of autosomal recessive inheritance. The patient reported night blindness at 4 years of age and exhibited typical RP fundus appearance with macula involvement during the follow-up period from at the age of 52–69 years. At the age of 52, the patient exhibited a loss of visual acuity and had severely constricted visual fields, with a further gradual deterioration of her vision until she was 69 years old. At the age of 69, funduscopy showed severe chorioretinal degeneration in the area from the posterior pole to the peripheral retina.Conclusions and ImportanceThis is the first report that the PDE6A variant (p.R653X) has been identified as one of the causes of autosomal recessive RP in the Japanese population. Longitudinal natural history/end-stage findings demonstrated early-onset and a severe RP phenotype with macula involvement when the patient was in her 50s and severe chorioretinal degenerations in her late 60s.

PDE6C: Novel Mutations, Atypical Phenotype, and Differences Among Children and Adults

“… 4 Rods have a PDE6 catalytic core composed of a heterodimer of PDE6A and PDE6B subunits (inhibited by PDE6G), whereas cones have a catalytic homodimer of PDE6C (inhibited by PDE6H subunits). 5 This explains why mutations in PDE6A (OMIM #180071), PDE6B (OMIM #180072) and PDE6G (OMIM #180073) cause autosomal recessive retinitis pigmentosa and autosomal dominant congenital stationary night blindness (both rod-related diseases), 6 , 7 whereas homozygous or compound heterozygous mutations in PDE6C and PDE6H (OMIM #600827 and #601190) lead to predominantly cone dysfunction disorders, such as achromatopsia (ACHM) and autosomal recessive cone dystrophy. 8 , 9 …”

Novel variants in PDE6A and PDE6B genes and its phenotypes in patients with retinitis pigmentosa in Chinese families

“… NA NA NA NA 0.0080% Yes [ 11 – 13 ] P03 PDE6A c.2275-2A > G p.? NA NA NA NA 0% Yes [ 14 ] PDE6A c.1957C > T p. Arg653* NA NA NA NA 0.0028% Yes [ 15 ] P04 PDE6A c.1747 T > A p. Tyr583Asn Possibly damaging Disease causing Tolerated Deleterious 0% No PDE6A c.1651A > G p. Lys551Glu Benign Disease causing Deleterious Deleterious 0% Yes [ 10 ] OPTN c.1634G > A p. Arg545Gln Benign Disease causing Tolerated Neutral 0.3103% Yes [ 16 , 17 ] P05 PDE6A c.1651A > G p. Lys551Glu Benign Disease causing Deleterious Deleterious 0% Yes [ 10 ] PDE6A c.285C > A p. Ser95Arg Possibly damaging Disease causing Deleterious Deleterious 0% Yes [ 10 ] P06 PDE6B c.401 T > C p. Leu134Pro Probably damaging Disease causing Deleterio...…”

Clinical features and treatment outcomes of a patient with retinitis pigmentosa secondary to adult coats' disease

“…RP used to be called pigmentary retinopathy, the typical clinical features are bilateral progressive peripheral visual eld defect, night blindness, retinal bone spicule intraretinal pigmentation,abnormal electroretinogram 6 and atrophy of RPE cells 5,7 . SRP, which also called pseudo-retinitis pigmentosa, is a kind of retinal degenerative diseases caused by primary disease, such as in ammation, trauma, retinal choroidal obstruction as well as ocular tumors 8 .…”