Variants in PAX6, PITX3 and HSF4 causing autosomal dominant congenital cataracts.

BACKGROUND: Lens development is orchestrated by transcription factors. Disease-causing variants in transcription factors and their developmental target genes are associated with congenital cataracts and other eye anomalies. METHODS: Using whole exome sequencing, we identified disease-causing variants in two large British families and one isolated case with autosomal dominant congenital cataract. Bioinformatics analysis confirmed these disease-causing mutations as rare or novel variants, with a moderate to damaging pathogenicity score, with testing for segregation within the families using direct Sanger sequencing. RESULTS: Family A had a missense variant (c.184 G>A; p.V62M) in PAX6 and affected individuals presented with nuclear cataract. Family B had a frameshift variant (c.470-477dup; p.A160R*) in PITX3 that was also associated with nuclear cataract. A recurrent missense variant in HSF4 (c.341 T>C; p.L114P) was associated with congenital cataract in a single isolated case. CONCLUSIONS: We have therefore identified novel variants in PAX6 and PITX3 that cause autosomal dominant congenital cataract.

Pathogenic variants in the CYP21A2 gene cause isolated autosomal dominant congenital posterior polar cataracts.

BACKGROUND: Congenital cataracts are the most common cause of visual impairment worldwide. Inherited cataract is a clinically and genetically heterogeneous disease. Here we report disease-causing variants in a novel gene, CYP21A2, causing autosomal dominant posterior polar cataract. Variants in this gene are known to cause autosomal recessive congenital adrenal hyperplasia (CAH). METHODS: Using whole-exome sequencing (WES), we have identified disease-causing sequence variants in two families of British and Irish origin, and in two isolated cases of Asian-Indian and British origin. Bioinformatics analysis confirmed these variants as rare with damaging pathogenicity scores. Segregation was tested within the families using direct Sanger sequencing. RESULTS: A nonsense variant NM_000500.9 c.955 C > T; p.Q319* was identified in CYP21A2 in two families with posterior polar cataract and in an isolated case with unspecified congenital cataract phenotype. This is the same variant previously linked to CAH and identified as Q318* in the literature. We have also identified a rare missense variant NM_000500.9 c.770 T > C; p.M257T in an isolated case with unspecified congenital cataract phenotype. CONCLUSION: This is the first report of separate sequence variants in CYP21A2 associated with congenital cataract. Our findings extend the genetic basis for congenital cataract and add to the phenotypic spectrum of CYP21A2 variants and particularly the CAH associated Q318* variant. CYP21A2 has a significant role in mineralo- and gluco-corticoid biosynthesis. These findings suggest that CYP21A2 may be important for extra-adrenal biosynthesis of aldosterone and cortisol in the eye lens.

The genetic landscape of crystallins in congenital cataract.

BACKGROUND: The crystalline lens is mainly composed of a large family of soluble proteins called the crystallins, which are responsible for its development, growth, transparency and refractive index. Disease-causing sequence variants in the crystallins are responsible for nearly 50% of all non-syndromic inherited congenital cataracts, as well as causing cataract associated with other diseases, including myopathies. To date, more than 300 crystallin sequence variants causing cataract have been identified. METHODS: Here we aimed to identify the genetic basis of disease in five multi-generation British families and five sporadic cases with autosomal dominant congenital cataract using whole exome sequencing, with identified variants validated using Sanger sequencing. Following bioinformatics analysis, rare or novel variants with a moderate to damaging pathogenicity score, were filtered out and tested for segregation within the families. RESULTS: We have identified 10 different heterozygous crystallin variants. Five recurrent variants were found: family-A, with a missense variant (c.145C>T; p.R49C) in CRYAA associated with nuclear cataract; family-B, with a deletion in CRYBA1 (c.272delGAG; p.G91del) associated with nuclear cataract; and family-C, with a truncating variant in CRYGD (c.470G>A; W157*) causing a lamellar phenotype; individuals I and J had variants in CRYGC (c.13A>C; T5P) and in CRYGD (c.418C>T; R140*) causing unspecified congenital cataract and nuclear cataract, respectively. Five novel disease-causing variants were also identified: family D harboured a variant in CRYGC (c.179delG; R60Qfs*) responsible for a nuclear phenotype; family E, harboured a variant in CRYBB1 (c.656G>A; W219*) associated with lamellar cataract; individual F had a variant in CRYGD (c.392G>A; W131*) associated with nuclear cataract; and individuals G and H had variants in CRYAA (c.454delGCC; A152del) and in CRYBB1 (c.618C>A; Y206*) respectively, associated with unspecified congenital cataract. All novel variants were predicted to be pathogenic and to be moderately or highly damaging. CONCLUSIONS: We report five novel variants and five known variants. Some are rare variants that have been reported previously in small ethnic groups but here we extend this to the wider population and record a broader phenotypic spectrum for these variants.

Whole Exome Sequencing Reveals Novel and Recurrent Disease-Causing Variants in Lens Specific Gap Junctional Protein Encoding Genes Causing Congenital Cataract.

Pediatric cataract is clinically and genetically heterogeneous and is the most common cause of childhood blindness worldwide. In this study, we aimed to identify disease-causing variants in three large British families and one isolated case with autosomal dominant congenital cataract, using whole exome sequencing. We identified four different heterozygous variants, three in the large families and one in the isolated case. Family A, with a novel missense variant (c.178G>C, p.Gly60Arg) in GJA8 with lamellar cataract; family B, with a recurrent variant in GJA8 (c.262C>T, p.Pro88Ser) associated with nuclear cataract; and family C, with a novel variant in GJA3 (c.771dupC, p.Ser258GlnfsTer68) causing a lamellar phenotype. Individual D had a novel variant in GJA3 (c.82G>T, p.Val28Leu) associated with congenital cataract. Each sequence variant was found to co-segregate with disease. Here, we report three novel and one recurrent disease-causing sequence variant in the gap junctional protein encoding genes causing autosomal dominant congenital cataract. Our study further extends the mutation spectrum of these genes and further facilitates clinical diagnosis. A recurrent p.P88S variant in GJA8 causing isolated nuclear cataract provides evidence of further phenotypic heterogeneity associated with this variant.

Opacification of Array SA40N silicone multifocal intraocular lens.

We report opacification of 2 multifocal intraocular lenses (IOLs). Patients with these IOLs may be more likely to require IOL explantation than those with monofocal IOLs.

Consequence of perforation during peribulbar anesthesia in an only eye.

A patient with a blind fellow eye had cataract surgery in the right eye; anesthesia comprised an intraocular injection of lidocaine and bupivacaine. Forty-eight hours after surgery, visual acuity in the right eye was light perception (LP). Three days later, fundus examination showed inferotemporal hemorrhage, retinal whitening consistent with needle tracking, and a diffusely pale optic disc in the operated eye. Computed tomography showed an intact optic nerve in both eyes and high-density vitreal lesions in the right eye. Laser photocoagulation was applied to the retinal break. We believe that a jet stream of anesthetic agent may have transiently increased intraocular volume enough to occlude the central retinal artery. Although the retina remained attached, visual acuity failed to improve beyond LP.

Effect of visual acuity on biometry prediction error after cataract surgery.

PURPOSE: To determine the effect of visual acuity on biometry prediction error. SETTING: Postgraduate teaching hospital. METHODS: The study was an observational case series of the first operated eye of 2149 consecutive patients who had cataract surgery. Biometry prediction error was defined as the difference between the planned refraction determined by biometry and the spherical equivalent of the final refraction. The principal outcome measure was the percentage of eyes within +/-1.00 diopter (D) of the intended refraction. This outcome was calculated for patients with visual loss caused by cataract alone, defined as eyes with a postoperative acuity of 6/6 or better, and eyes with different levels of postoperative visual acuity. RESULTS: Complete data were available for 1978 eyes (92%). Of these, 1438 (73%) were within +/-1.00 D of the intended refraction. When the final corrected visual acuity was 6/6 or better, the percentage of eyes within +/-1.00 D of the predicted refraction was at least 78%. When the preoperative acuity was worse than 6/60, 74% in the counting fingers group and 69% in the hand movements group with a final corrected acuity of 6/6 or better were within +/-1.00 D. This trend bordered on statistical significance (P =.05). There was a rapid reduction in the percentage of eyes within +/-1.00 D of the intended refraction as the postoperative acuity decreased because of ocular comorbidity, with a statistically significant difference between eyes with a postoperative acuity of 6/6 or better and each group with an acuity of 6/9 or worse (P<.01). CONCLUSIONS: In eyes without visually significant ocular comorbidity, cataract must reduce vision to 6/60 or worse before there is an increase in biometry prediction error. In contrast, ocular comorbidity that reduces the postoperative acuity causes an early and marked increase in biometry prediction error.