Multimorbidity due to novel pathogenic variants in the WFS1/RP1/NOD2 genes: autosomal dominant congenital lamellar cataract, retinitis pigmentosa and Crohn's disease in a British family.

BACKGROUND: A five generation family has been analysed by whole exome sequencing (WES) for genetic associations with the multimorbidities of congenital cataract (CC), retinitis pigmentosa (RP) and Crohn's disease (CD). METHODS: WES was performed for unaffected and affected individuals within the family pedigree followed by bioinformatic analyses of these data to identify disease-causing variants with damaging pathogenicity scores. RESULTS: A novel pathogenic missense variant in WFS1: c.1897G>C; p.V633L, a novel pathogenic nonsense variant in RP1: c.6344T>G; p.L2115* and a predicted pathogenic missense variant in NOD2: c.2104C>T; p.R702W are reported. The three variants cosegregated with the phenotypic combinations of autosomal dominant CC, RP and CD within individual family members. CONCLUSIONS: Here, we report multimorbidity in a family pedigree listed on a CC register, which broadens the spectrum of potential cataract associated genes to include both RP1 and NOD2.

Cataract surgery outcomes in eyes with previous radial keratotomy.

BACKGROUND/OBJECTIVES: This study shows the visual and refractive outcomes of cataract surgery in patients with previous radial keratotomy (RK). SUBJECTS/METHODS: This is a retrospective case series of 100 eyes (65 patients) with previous RK who had undergone routine cataract surgery with a monofocal intraocular lens implant (IOL) at Moorfields Eye Hospital, London, United Kingdom, between January 2004 and December 2018. RESULTS: Mean age at the time of surgery was 59.8 years; 39% eyes had ocular copathology. Best-corrected visual acuity (LogMAR; median, interquartile range) improved from 0.30 (0.22, 0.55) to 0.06 (-0.02, 0.21) in eyes without copathology, and from 0.56 (0.30, 1.00) to 0.20 (0.00, 0.20) in eyes with copathology. Haigis formula (19 eyes) resulted in a median prediction error of -0.31 D (-1.07, +0.05), versus -0.55 D (-1.23, +0.22) for Double-K SRK/T (55 eyes) and +0.93 D (0.20, 2.31) for SRK/T (18 eyes). At the final follow-up, 52.6% eyes were within 0.5 D and 68.4% within 1 D of the predicted spherical equivalent for Haigis, versus 32.7% and 52.7% for Double-K SRK/T, and 27.8% and 38.9% for SRK/T. The most frequent complication was RK incision dehiscence (8%). CONCLUSIONS: Although the best-corrected visual acuity outcomes compare with the UK national benchmarks, significantly fewer eyes with previous RK achieved the level of unaided distance visual acuity to allow spectacle independence. Surgeons should be aware of the increased likelihood of wound dehiscence and plan surgery accordingly. Haigis formula tended to have a better predictability of the postoperative spherical equivalent and, since introduced, was the preferred choice for IOL calculation in this group of patients.

Whole-genome sequencing reveals a recurrent missense mutation in the Connexin 46 (GJA3) gene causing autosomal-dominant lamellar cataract.

PURPOSE: Congenital cataract, opacification of the ocular lens, is clinically and genetically a heterogeneous childhood disease. In this study we aimed to identify the underlying genetic cause of isolated autosomal-dominant lamellar cataract in a multi-generation English family. METHODS: Whole-genome sequencing (WGS) was undertaken in two affected subjects and one unaffected individual. Segregation analysis was performed and a known cataract-causing mutation was identified. Segregation was further validated by sanger sequencing in the entire pedigree. RESULTS: A heterozygous mutation c.7 G > T; p.D3Y was identified in an NH2-terminal region of the gap junction protein GJA3 and found to co-segregate with disease. CONCLUSION: We have identified a recurrent mutation in GJA3 in a large British pedigree causing the novel phenotype of autosomal-dominant congenital lamellar cataract. Previously, p.D3Y was found in a Hispanic family causing pulverulent cataract. WGS proved an efficient method to find the underlying molecular cause in this large family, which could not be mapped due to uninformative markers.

A novel locus for autosomal dominant congenital cerulean cataract maps to chromosome 12q.

Cataracts are the commonest cause of blindness worldwide. Inherited cataract is a clinically and genetically heterogeneous disease that most often shows autosomal dominant inheritance. In this study, we report the identification of a novel locus for cerulean cataract type 5 (CCA5), also known as blue-dot cataract on chromosome 12q24. To date, four loci for autosomal dominant congenital cerulean cataract have been mapped on chromosomes, 17q24, 22q11.2-12.2, 2q33-35 and 16q23.1. To map this locus we performed genetic linkage analysis using microsatellite markers in a five-generation English family. After the exclusion of all known loci and several candidate genes we obtained significantly positive LOD score (Z) for marker D12S1611 (Z(max)=3.60; at θ=0). Haplotype data indicated that CCA5 locus lies within a region of 14.3 Mb interval between the markers D12S1718 and D12S1723. Our data are strongly suggestive of a new locus for CCA5 on chromosome 12.

Internal carotid artery dissection secondary to excessive vocal output.

A previously healthy 61-year-old male presented to eye casualty with a left-sided Horner's syndrome. He reported that while offering strong vocal support at a football match 5 days previously, he had suddenly noticed an unusual sensation behind his left eye, accompanied by a left hemifacial headache. He had noted pupillary asymmetry soon after this. Radiological imaging revealed a left internal carotid artery dissection. Anticoagulant therapy was commenced, and all symptoms and signs had fully resolved at 1-month follow-up, with no further complications.