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Molecular and Genetic Mechanism of Non-Syndromic Congenital Cataracts

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Molecular and Genetic Mechanism of Non-Syndromic Congenital Cataracts G C A T T A C G G C A T genes Article Molecular and Genetic Mechanism of Non-Syndromic Congenital Cataracts. Mutation Screening in Spanish Families Celia Fernández-Alcalde 1,* , María Nieves-Moreno 1, Susana Noval 1 , Jesús M. Peralta 1, Victoria E. F. Montaño 2, Ángela del Pozo 3, Fernando Santos-Simarro 4 and Elena Vallespín 2 1 Department of Ophthalmology, Hospital Universitario La Paz, 28046 Madrid, Spain; [email protected] (M.N.-M.); [email protected] (S.N.); [email protected] (J.M.P.) 2 Department of Molecular Ophthalmology, Medical and Molecular Genetics Institute (INGEMM) IdiPaz, CIBERER, Hospital Universitario La Paz, 28046 Madrid, Spain; [email protected] (V.E.F.M.); [email protected] (E.V.) 3 Department of Clinical Bioinformatics, Medical and Molecular Genetics Institute (INGEMM) IdiPaz, CIBERER, Hospital Universitario La Paz, 28046 Madrid, Spain; [email protected] 4 Department of Clinical Genetics, Medical and Molecular Genetics Institute (INGEMM) IdiPaz, CIBERER, Hospital Universitario La Paz, 28046 Madrid, Spain; [email protected] * Correspondence: [email protected] Abstract: Our purpose was to identify mutations responsible for non-syndromic congenital cataracts through the implementation of next-generation sequencing (NGS) in our center. A sample of peripheral blood was obtained from probands and willing family members and genomic DNA was extracted from leukocytes. DNA was analyzed implementing a panel (OFTv2.1) including 39 known congenital Citation: Fernández-Alcalde, C.; cataracts disease genes. 62 probands from 51 families were recruited. Pathogenic or likely pathogenic Nieves-Moreno, M.; Noval, S.; Peralta, variants were identified in 32 patients and 25 families; in 16 families (64%) these were de novo J.M.; Montaño, V.E.F.; del Pozo, Á.; mutations. The mutation detection rate was 49%. Almost all reported mutations were autosomal Santos-Simarro, F.; Vallespín, E. dominant. Mutations in crystallin genes were found in 30% of the probands. Mutations in membrane Molecular and Genetic Mechanism of proteins were detected in seven families (two in GJA3 and five in GJA8). Mutations in LIM2 and MIP Non-Syndromic Congenital Cataracts. were each found in three families. Other mutations detected affected EPHA2, PAX6, HSF4 and PITX3. Mutation Screening in Spanish Variants classified as of unknown significance were found in 5 families (9.8%), affecting CRYBB3, LIM2, Families. Genes 2021, 12, 580. EPHA2, ABCB6 and TDRD7. Mutations lead to different cataract phenotypes within the same family. https://doi.org/10.3390/genes12040580 Keywords: congenital cataracts; genetics; next-generation sequencing; ophthalmogenetics Academic Editor: Alessandro Iannaccone Received: 16 March 2021 Accepted: 14 April 2021 1. Introduction Published: 16 April 2021 The ocular lens is part of the anterior segment of the human eye. As part of the refractive system, its main function is to transmit and focus light onto the retina due to Publisher’s Note: MDPI stays neutral its transparency, shape and accommodative power [1–3]. Proteins represent up to 60% with regard to jurisdictional claims in of the lens mass, mostly as lens crystallins, whose distribution and stability are critical published maps and institutional affil- for light transmission [4,5]. Any disturbance in the cell structure will produce diffraction, iations. absorbance or reflection of the light, which will result in diminished vision [6]. A cataract is an opacity of the lens [7]. Congenital or infantile cataracts present within the first year of life and are considered to be the main cause of treatable blindness during infancy worldwide. Reported incidence ranges from 12 to 136 per 100,000 births, with Copyright: © 2021 by the authors. higher rates in under-developed countries [8]. Congenital cataracts can be caused by Licensee MDPI, Basel, Switzerland. connatal infections, fetal suffering or genetic variations. It is estimated that 8.3–25% of This article is an open access article congenital cataracts are hereditary [9]; remarkably, they were the first autosomal disease distributed under the terms and mapped in humans [10]. Hereditary cataracts can be divided into two groups: syndromic conditions of the Creative Commons cataracts, which form part of a systemic disease affecting other tissues, and non-syndromic Attribution (CC BY) license (https:// cataracts, in cases in which the lens is the only compromised organ. It is important to creativecommons.org/licenses/by/ understand that cataract phenotype is not a reliable indicator of the affected gene or 4.0/). Genes 2021, 12, 580. https://doi.org/10.3390/genes12040580 https://www.mdpi.com/journal/genes Genes 2021, 12, x FOR PEER REVIEW 2 of 13 to understand that cataract phenotype is not a reliable indicator of the affected gene or mutation, since identical cataracts can be caused by mutations at different loci; the same mutation can also cause different types of cataracts [10–15]. Genes 2021, 12, 580 2 of 13 Currently, the only treatment for congenital cataracts is surgery, with the removal of the opacified lens. Early intervention is crucial due to the high risk of amblyopia. Cataract surgerymutation, in sincebabies identical and infants cataracts has a can high be risk caused of postoperative by mutations atcomplications different loci; and the it same is a challengemutation to can achieve also cause a good different visual typesacuity of despite cataracts timely [10– intervention15]. and adequate follow- up [16–20].Currently, the only treatment for congenital cataracts is surgery, with the removal of the opacifiedMutations lens. causing Early congenital intervention cataracts is crucial affect due the to theprocess high riskof protein of amblyopia. aggregation Cataract and involvesurgery the in babiesbreakdown and infantsof lens architecture. has a high risk All three of postoperative types of Mendelian complications inheritance and pat- it is ternsa challenge have been to achieve reported, a goodalthough visual the acuity most frequent despite timelyis autosomal intervention dominant and with adequate high penetrance.follow-up [16 There–20]. may be remarkable phenotype variability within a family and even be- tweenMutations the two lenses causing of congenitalthe same individual cataractsaffect (Figure the 1a process polar cataract; of protein Figure aggregation 1b nuclear and cataract).involve the Mutations breakdown in over of lens52 genes architecture. have been All described three types so far, of 35 Mendelian associated inheritance with non- syndromicpatterns have congenital been reported, cataracts although and 17 which the most may frequentcause either is autosomalsyndromic dominantor isolated with cat- aracts.high penetrance. Mutations Therecan be may divided be remarkable depending phenotype on the proteins variability affected within into a familyfour main and groups:even between lens crystallins the two lenses(37%), ofmembrane the same proteins individual (22%), (Figure transcription1a polar cataract; factors (14%) Figure and1b cytoskeletalnuclear cataract). proteins Mutations (3–7%) in[21–25]. over 52 genes have been described so far, 35 associated with non-syndromicThe purpose congenital of this study cataracts is to identify and 17 which the mutations may cause leading either to syndromic the development or isolated of non-syndromiccataracts. Mutations congenital can be cataracts divided in depending our hospital, on which the proteins is one of affected the main into referral four main cen- tersgroups: for the lens diagnosis crystallins and (37%), treatment membrane of this proteins pathology (22%), in Spain, transcription through factors the implementa- (14%) and tioncytoskeletal of next-generation proteins (3–7%) sequencing [21–25 ].(NGS) for mutation screening. (a) (b) Figure 1. ((aa)) Polar Polar anterior anterior cong congenitalenital cataract; ( b) Nuclear congenital cataract. 2. ObjectivesThe purpose of this study is to identify the mutations leading to the development of -non-syndromic To evaluate congenital the implementation cataracts in ourof NGS hospital, for mutation which is onescreening of the main in congenital referral centers cata- for theracts diagnosis at a tertiary and treatmenthospital in of Spain. this pathology in Spain, through the implementation of -next-generation To identify sequencingthe mutations (NGS) that for produce mutation congenital screening. cataracts in Spain and compare them with those reported for other populations. 2. Objectives 3.- ResultsTo evaluate the implementation of NGS for mutation screening in congenital cataracts at a tertiary hospital in Spain. A total of 62 probands from 51 families diagnosed with non-syndromic congenital - To identify the mutations that produce congenital cataracts in Spain and compare cataracts were recruited. After performing NGS analysis with a specifically designed them with those reported for other populations. panel, we identified pathogenic or likely pathogenic variants in 32 patients and 25 fami- lies:3. Results this represents a mutation detection rate of 49% (Tables 1 and 2). Variants classified as a variant of unknown significance (VUS) were found in seven patients and five families A total of 62 probands from 51 families diagnosed with non-syndromic congenital (9.8%).cataracts were recruited. After performing NGS analysis with a specifically designed panel, we identifiedGender distribution pathogenic was or likely 35.5% pathogenic of male an variantsd
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