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Matthew C Weed, Scott R Lambert, Scott A Larson, Richard J Olson, Susannah Q Longmuir, Adam P DeLuca, Elizabeth L Kennedy, Edwin M Stone, Arlene V Drack; Genetic testing for congenital cataract. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2526. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Congenital cataracts may be isolated or syndromic. The large number of causative genes and various inheritance patterns make genetic testing complex. Some disorders, such as cerebrotendinous xanthomatosis (CTX), require early detection to allow preventive treatment for life-threatening comorbidities. We present a genetic testing strategy for congenital cataract.
IRB approval was obtained. Congenital cataract patients presenting to two pediatric ophthalmology services were offered research-based genetic testing. Literature review of causative mutations published at least twice was used to develop a Sanger sequencing pre-screen of 24 exons in 11 genes (BFSP2, CRYAA, CRYBA1, BRYBB2, CRYGD, EPHA2, FAM126A, FYCO1, NHS, PAX6 and VSX2). Patients with a negative pre-screen received exome sequencing followed by lens-related analysis. Potential disease-causing variants were verified by Sanger sequencing. Allele frequency, mutation type, and familial segregation were used to predict pathogenicity.
Thirty-three probands submitted samples. Pre-screening identified probable causative variants in 4 families and possible causative variants in 2 families (CRYBA1(1), CRYGD(3), NHS(1) CRYAA(1)). Twenty-three probands had exome sequencing data. Eighteen of these had protein-altering mutations in one or more lens-related genes (range 0-3) (BFSP1, CHMP4B, COL11A1, CRBB1, CRYBA1, CRYBA4, CRYBB2, CRYGS, FOXE3, EPHA2, EYA1, FYCO1, GJA8, MP3, NHS, PITX3 and VSX2). Five families had variants that were supported by segregation. Two families with plausible disease-causing variants identified by exome sequencing failed to segregate properly within the family, emphasizing the importance of segregation analysis prior to concluding pathogenicity. Fifteen of 689 control samples had exonic single allele mutations in CYP27A1; none of the 28 cataract samples had mutations in this gene.
Exome sequencing is useful for heterogeneous diseases like congenital cataract. However, non-disease-causing variants are common, thus all variants must be carefully scrutinized to confirm pathogenicity. Pre-screening for known disease-causing mutations decreases cost and increases efficiency. Mutations in CYP27A1 are uncommon in controls and can be screened in cataract patients for early detection of CTX. Early genetic testing allows differentiation between isolated and syndromic cataracts, improved prognostic and genetic counseling, and systemic treatment when required.
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