{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:14:05Z","timestamp":1790475245415,"version":"4.1.0"},"reference-count":84,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T00:00:00Z","timestamp":1609891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Iten-Kohaut-Foundation","award":["no grant number"],"award-info":[{"award-number":["no grant number"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Coloboma and microphthalmia (C\/M) are related congenital eye malformations, which can cause significant visual impairment. Molecular diagnosis is challenging as the genes associated to date with C\/M account for only a small percentage of cases. Overall, the genetic cause remains unknown in up to 80% of patients. High throughput DNA sequencing technologies, including whole-exome sequencing (WES), are therefore a useful and efficient tool for genetic screening and identification of new mutations and novel genes in C\/M. In this study, we analyzed the DNA of 19 patients with C\/M from 15 unrelated families using singleton WES and data analysis for 307 genes of interest. We identified seven novel and one recurrent potentially disease-causing variants in CRIM1, CHD7, FAT1, PTCH1, PUF60, BRPF1, and TGFB2 in 47% of our families, three of which occurred de novo. The detection rate in patients with ocular and extraocular manifestations (67%) was higher than in patients with an isolated ocular phenotype (46%). Our study highlights the significant genetic heterogeneity in C\/M cohorts and emphasizes the diagnostic power of WES for the screening of patients and families with C\/M.<\/jats:p>","DOI":"10.3390\/genes12010065","type":"journal-article","created":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T09:15:16Z","timestamp":1609924516000},"page":"65","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Whole Exome Sequencing in Coloboma\/Microphthalmia: Identification of Novel and Recurrent Variants in Seven Genes"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6160-3177","authenticated-orcid":false,"given":"Patricia","family":"Haug","sequence":"first","affiliation":[{"name":"Institute of Medical Molecular Genetics, University of Zurich, 8952 Schlieren, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0965-0539","authenticated-orcid":false,"given":"Samuel","family":"Koller","sequence":"additional","affiliation":[{"name":"Institute of Medical Molecular Genetics, University of Zurich, 8952 Schlieren, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9906-8739","authenticated-orcid":false,"given":"Jordi","family":"Maggi","sequence":"additional","affiliation":[{"name":"Institute of Medical Molecular Genetics, University of Zurich, 8952 Schlieren, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Lang","sequence":"additional","affiliation":[{"name":"Institute of Medical Molecular Genetics, University of Zurich, 8952 Schlieren, Switzerland"},{"name":"Department of Ophthalmology, University Hospital and University of Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Feil","sequence":"additional","affiliation":[{"name":"Institute of Medical Molecular Genetics, University of Zurich, 8952 Schlieren, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agn\u00e8s","family":"Wlodarczyk","sequence":"additional","affiliation":[{"name":"Institute of Medical Molecular Genetics, University of Zurich, 8952 Schlieren, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luzy","family":"B\u00e4hr","sequence":"additional","affiliation":[{"name":"Institute of Medical Molecular Genetics, University of Zurich, 8952 Schlieren, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Steindl","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics, University of Zurich, 8952 Schlieren, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4013-6012","authenticated-orcid":false,"given":"Marianne","family":"Rohrbach","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children\u2019s Research Centre, University Children\u2019s Hospital Zurich, 8032 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6298-615X","authenticated-orcid":false,"given":"Christina","family":"Gerth-Kahlert","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital and University of Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0370-3815","authenticated-orcid":false,"given":"Wolfgang","family":"Berger","sequence":"additional","affiliation":[{"name":"Institute of Medical Molecular Genetics, University of Zurich, 8952 Schlieren, Switzerland"},{"name":"Neuroscience Center Zurich (ZNZ), University and ETH Zurich, 8006 Zurich, Switzerland"},{"name":"Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8006 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.ejmg.2014.05.002","article-title":"The genetic architecture of microphthalmia, anophthalmia and coloboma","volume":"57","author":"Williamson","year":"2014","journal-title":"Eur. J. Med. Genet."},{"key":"ref_2","first-page":"865","article-title":"An update on the genetics of ocular coloboma","volume":"138","author":"Alsomiry","year":"2019","journal-title":"Qual. Life Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1097\/01.icu.0000243020.82380.f6","article-title":"Uveal coloboma: Clinical and basic science update","volume":"17","author":"Chang","year":"2006","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1001\/archopht.1989.01070020697031","article-title":"Complex Microphthalmos","volume":"107","author":"Weiss","year":"1989","journal-title":"Arch. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1001\/archopht.1989.01070020703032","article-title":"Simple Microphthalmos","volume":"107","author":"Weiss","year":"1989","journal-title":"Arch. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1136\/jmg.39.1.16","article-title":"National study of microphthalmia, anophthalmia, and coloboma (MAC) in Scotland: Investigation of genetic aetiology","volume":"39","author":"Davenport","year":"2002","journal-title":"J. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s10654-004-6880-1","article-title":"The epidemiology of anophthalmia and microphthalmia in Sweden","volume":"20","author":"Tornqvist","year":"2005","journal-title":"Eur. J. Epidemiol."},{"key":"ref_8","first-page":"799","article-title":"Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia\/microphthalmia","volume":"138","author":"Ceroni","year":"2019","journal-title":"Qual. Life Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1076\/0928-6586(200006)721-ZFT127","article-title":"Regional variation in blindness in children due to microphthalmos, anophthalmos and coloboma","volume":"7","author":"Hornby","year":"2000","journal-title":"Ophthalmic Epidemiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1002\/(SICI)1096-8628(19980217)75:5<497::AID-AJMG8>3.0.CO;2-K","article-title":"Congenital eye malformations: Clinical-epidemiological analysis of 1,124,654 consecutive births in Spain","volume":"75","author":"Bermejo","year":"1998","journal-title":"Am. J. Med. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/ajmg.a.30840","article-title":"Epidemiologic characteristics of anophthalmia and bilateral microphthalmia among 2.5 million births in California, 1989\u20131997","volume":"137","author":"Shaw","year":"2005","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/0890-6238(94)90079-5","article-title":"Anophthalmia and benomyl in Italy: A multicenter study based on 940,615 newborns","volume":"8","author":"Spagnolo","year":"1994","journal-title":"Reprod. Toxicol."},{"key":"ref_13","first-page":"231","article-title":"Prevalence and mode of inheritance of major genetic eye diseases in China","volume":"15","author":"Hu","year":"1988","journal-title":"Acta Genet. Sin."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1167\/iovs.10-5263","article-title":"Anophthalmos, Microphthalmos, and Typical Coloboma in the United Kingdom: A Prospective Study of Incidence and Risk","volume":"52","author":"Shah","year":"2011","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1002\/bdrc.21097","article-title":"Conserved genetic pathways associated with microphthalmia, anophthalmia, and coloboma","volume":"105","author":"Reis","year":"2015","journal-title":"Birth Defects Res. Part C Embryo Today Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1055\/s-0036-1592350","article-title":"Genetic Advances in Microphthalmia","volume":"5","author":"Plaisancie","year":"2016","journal-title":"J. Pediatr. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/mgg3.2","article-title":"Clinical and mutation analysis of 51 probands with anophthalmia and\/or severe microphthalmia from a single center","volume":"1","author":"Williamson","year":"2013","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1093\/hmg\/ddw020","article-title":"A secreted WNT-ligand-binding domain of FZD5 generated by a frameshift mutation causes autosomal dominant coloboma","volume":"25","author":"Liu","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.ymgme.2010.03.004","article-title":"Next generation sequencing in research and diagnostics of ocular birth defects","volume":"100","author":"Raca","year":"2010","journal-title":"Mol. Genet. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1167\/tvst.9.7.47","article-title":"Exome Sequencing in a Swiss Childhood Glaucoma Cohort Reveals CYP1B1 and FOXC1 Variants as Most Frequent Causes","volume":"9","author":"Lang","year":"2020","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1093\/nar\/gkj518","article-title":"Computational approaches for predicting the biological effect of p53 missense mutations: A comparison of three sequence analysis based methods","volume":"34","author":"Mathe","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1093\/bioinformatics\/btv009","article-title":"An integrative approach to predicting the functional effects of non-coding and coding sequence variation","volume":"31","author":"Shihab","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: Predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: Mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"W452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT web server: Predicting effects of amino acid substitutions on proteins","volume":"40","author":"Sim","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1002\/humu.22106","article-title":"A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome","volume":"33","author":"Bergman","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1093\/hmg\/ddu733","article-title":"Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies","volume":"24","author":"Dong","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Maggi, J., Koller, S., B\u00e4hr, L., Feil, S., Pfiffner, F.K., Hanson, J.V.M., Maspoli, A., Gerth-Kahlert, C., and Berger, W. (2020). Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases. MedRxiv.","DOI":"10.1101\/2020.11.30.20234971"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1002\/humu.20747","article-title":"Transcriptional expression ofcis-acting andtrans-acting splicing mutations cause autosomal dominant retinitis pigmentosa","volume":"29","author":"Gamundi","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_30","first-page":"93","article-title":"Progressive Sensorineural Hearing Loss and Normal Vestibular Function in a Dutch DFNB7\/11 Family with a Novel Mutation in TMC1","volume":"16","author":"Collin","year":"2010","journal-title":"Audiol. Neurotol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1136\/jmg.2005.036061","article-title":"CHARGE syndrome: The phenotypic spectrum of mutations in the CHD7 gene","volume":"43","author":"Jongmans","year":"2005","journal-title":"J. Med. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1530\/EJE-18-0764","article-title":"New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism","volume":"181","author":"Amato","year":"2019","journal-title":"Eur. J. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1002\/humu.22086","article-title":"Mutation update on the CHD7 gene involved in CHARGE syndrome","volume":"33","author":"Janssen","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1016\/j.ophtha.2011.01.028","article-title":"Structural Grading of Foveal Hypoplasia Using Spectral-Domain Optical Coherence Tomography","volume":"118","author":"Thomas","year":"2011","journal-title":"Ophthalmology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1093\/hmg\/ddu744","article-title":"CRIM1 haploinsufficiency causes defects in eye development in human and mouse","volume":"24","author":"Beleggia","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3109\/13816818409007839","article-title":"Colobomatous macrophthalmia with microcornea","volume":"4","author":"Bateman","year":"1984","journal-title":"Ophthalmic Paediatr. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Ponferrada, V.G., Fan, J., Vallance, J.E., Hu, S., Mamedova, A., Rankin, S.A., Kofron, M., Zorn, A.M., Hegde, R.S., and Lang, R.A. (2012). CRIM1 Complexes with \u00df-catenin and Cadherins, Stabilizes Cell-Cell Junctions and Is Critical for Neural Morphogenesis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0032635"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1002\/ajmg.a.20083","article-title":"Colobomatous macrophthalmia with microcornea syndrome: Report of a new pedigree","volume":"121","author":"Toker","year":"2003","journal-title":"Am. J. Med. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1038\/s41431-019-0465-7","article-title":"A functional assay to study the pathogenicity of CHD7 protein variants encountered in CHARGE syndrome patients","volume":"27","author":"Brajadenta","year":"2019","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Verloes, A. (2005). Updated diagnostic criteria for CHARGE syndrome: A proposal. Am. J. Med. Genet. Part A, 306\u2013308.","DOI":"10.1002\/ajmg.a.30559"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1002\/ajmg.a.33323","article-title":"Molecular and phenotypic aspects ofCHD7mutation in CHARGE syndrome","volume":"152A","author":"Zentner","year":"2010","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"10822","DOI":"10.1038\/ncomms10822","article-title":"FAT1 mutations cause a glomerulotubular nephropathy","volume":"7","author":"Gee","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1038\/s41467-019-08547-w","article-title":"Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly","volume":"10","author":"Lahrouchi","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.ajhg.2013.10.011","article-title":"Loss-of-Function Mutations in TBC1D20 Cause Cataracts and Male Infertility in blind sterile Mice and Warburg Micro Syndrome in Humans","volume":"93","author":"Liegel","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1002\/humu.22760","article-title":"Identification of Variants in the 4q35 GeneFAT1in Patients with a Facioscapulohumeral Dystrophy-Like Phenotype","volume":"36","author":"Puppo","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1002\/bdra.23072","article-title":"Epithelial fusion during neural tube morphogenesis","volume":"94","author":"Pai","year":"2012","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1083\/jcb.200403006","article-title":"Mammalian Fat1 cadherin regulates actin dynamics and cell\u2013cell contact","volume":"165","author":"Tanoue","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4099","DOI":"10.1167\/iovs.15-17008","article-title":"Atypical Cadherin Fat1 Is Required for Lens Epithelial Cell Polarity and Proliferation but Not for Fiber Differentiation","volume":"56","author":"Sugiyama","year":"2015","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Vona, B., Nanda, I., Neuner, C., Schr\u00f6der, J., Kalscheuer, V.M., Shehata-Dieler, W., and Haaf, T. (2014). Terminal chromosome 4q deletion syndrome in an infant with hearing impairment and moderate syndromic features: Review of literature. BMC Med. Genet., 15.","DOI":"10.1186\/1471-2350-15-72"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Caruso, N., Herberth, B., Bartoli, M., Puppo, F., Dumonceaux, J., Zimmermann, A., Denadai, S., Leboss\u00e9, M., Roche, S., and Geng, L. (2013). Deregulation of the Protocadherin Gene FAT1 Alters Muscle Shapes: Implications for the Pathogenesis of Facioscapulohumeral Dystrophy. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003550"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1242\/dev.077461","article-title":"Functional interactions between Fat family cadherins in tissue morphogenesis and planar polarity","volume":"139","author":"Saburi","year":"2012","journal-title":"Development"},{"key":"ref_52","first-page":"881","article-title":"The genetic architecture of aniridia and Gillespie syndrome","volume":"138","author":"Hall","year":"2019","journal-title":"Qual. Life Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1136\/bjo.2004.061390","article-title":"Gorlin syndrome: The PTCH gene links ocular developmental defects and tumour formation","volume":"89","author":"Ragge","year":"2005","journal-title":"Br. J. Ophthalmol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1101\/gr.196048.115","article-title":"Targeted resequencing identifiesPTCH1as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network","volume":"26","author":"Chassaing","year":"2016","journal-title":"Genome Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1002\/ajmg.a.34128","article-title":"Consensus statement from the first international colloquium on basal cell nevus syndrome (BCNS)","volume":"155","author":"Bree","year":"2011","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3269","DOI":"10.1093\/hmg\/ddg356","article-title":"Abnormalities of the vitreoretinal interface caused by dysregulated Hedgehog signaling during retinal development","volume":"12","author":"Black","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.gene.2004.01.010","article-title":"Expression of the PTCH1 tumor suppressor gene is regulated by alternative promoters and a single functional Gli-binding site","volume":"330","author":"Kogerman","year":"2004","journal-title":"Gene"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"24e","DOI":"10.1136\/jmg.39.5.e24","article-title":"Comparative genomic hybridisation shows a partial de novo deletion 16p11.2 in a neonate with multiple congenital malformations","volume":"39","author":"Hernando","year":"2002","journal-title":"J. Med. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1136\/jmg.2009.073015","article-title":"Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size","volume":"47","author":"Shinawi","year":"2009","journal-title":"J. Med. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1038\/ejhg.2010.168","article-title":"Expanding the clinical spectrum of the 16p11.2 chromosomal rearrangements: Three patients with syringomyelia","volume":"19","author":"Schaaf","year":"2010","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1002\/pd.5245","article-title":"Intrauterine phenotypic features associated with 16p11.2 recurrent microdeletions","volume":"38","author":"Lin","year":"2018","journal-title":"Prenat. Diagn."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3120","DOI":"10.1002\/ajmg.a.33492","article-title":"Clinical report of microphthalmia and optic nerve coloboma associated with a de novo microdeletion of chromosome 16p11.2","volume":"152","author":"Bardakjian","year":"2010","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1080\/13816810.2017.1318927","article-title":"A de novo PUF60 mutation in a child with a syndromic form of coloboma and persistent fetal vasculature","volume":"38","author":"Graziano","year":"2017","journal-title":"Ophthalmic Genet."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/ejhg.2017.27","article-title":"PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features","volume":"25","author":"Low","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1016\/j.ajhg.2013.09.010","article-title":"SCRIB and PUF60 Are Primary Drivers of the Multisystemic Phenotypes of the 8q24.3 Copy-Number Variant","volume":"93","author":"Dauber","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"103691","DOI":"10.1016\/j.ejmg.2019.103691","article-title":"Novel BRPF1 mutation in a boy with intellectual disability, coloboma, facial nerve palsy and hypoplasia of the corpus callosum","volume":"62","author":"Demeulenaere","year":"2019","journal-title":"Eur. J. Med. Genet."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.ajhg.2016.11.010","article-title":"Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis","volume":"100","author":"Mattioli","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ajhg.2016.11.011","article-title":"Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation","volume":"100","author":"Yan","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"7114","DOI":"10.1074\/jbc.M114.635250","article-title":"Deficiency of the Chromatin Regulator Brpf1 Causes Abnormal Brain Development","volume":"290","author":"You","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.cca.2014.07.016","article-title":"Whole exome sequencing for the identification of a new mutation in TGFB2 involved in a familial case of non-syndromic aortic disease","volume":"437","author":"Valenzuela","year":"2014","journal-title":"Clin. Chim. Acta"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1038\/ng.2349","article-title":"Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm","volume":"44","author":"Lindsay","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/gim.2014.11","article-title":"Loeys\u2013Dietz syndrome: A primer for diagnosis and management","volume":"16","author":"MacCarrick","year":"2014","journal-title":"Genet. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1098\/rsob.170134","article-title":"TGF\u03b2-facilitated optic fissure fusion and the role of bone morphogenetic protein antagonism","volume":"8","author":"Knickmeyer","year":"2018","journal-title":"Open Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2659","DOI":"10.1242\/dev.124.13.2659","article-title":"TGF\u03b22 Knockout Mice Have Multiple Developmental Defects That Are Non-Overlapping with Other TGF\u03b2 Knockout Phenotypes","volume":"124","author":"Sanford","year":"1997","journal-title":"Development"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1038\/s41431-019-0479-1","article-title":"Anophthalmia including next-generation sequencing-based approaches","volume":"28","author":"Harding","year":"2019","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/1750-1172-2-47","article-title":"Anophthalmia and microphthalmia","volume":"2","author":"Verma","year":"2007","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1111\/cge.12275","article-title":"Molecular findings and clinical data in a cohort of 150 patients with anophthalmia\/microphthalmia","volume":"86","author":"Chassaing","year":"2013","journal-title":"Clin. Genet."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/ejhg.2015.155","article-title":"Novel mutations in PAX6, OTX2 and NDP in anophthalmia, microphthalmia and coloboma","volume":"24","author":"Deml","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1136\/bjo.2009.173500","article-title":"Mutational screening of CHX10, GDF6, OTX2, RAX and SOX2 genes in 50 unrelated microphthalmia-anophthalmia-coloboma (MAC) spectrum cases","volume":"94","author":"Pelcastre","year":"2010","journal-title":"Br. J. Ophthalmol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Jimenez, N.L., Flannick, J., Yahyavi, M., Li, J., Bardakjian, T.M., Tonkin, L., Schneider, A., Sherr, E., and Slavotinek, A.M. (2011). Targeted \u2019Next-Generation\u2019 sequencing in anophthalmia and microphthalmia patients confirms SOX2, OTX2 and FOXE3 mutations. BMC Med. Genet., 12.","DOI":"10.1186\/1471-2350-12-172"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1111\/cge.12543","article-title":"Exome sequencing in 32 patients with anophthalmia\/microphthalmia and developmental eye defects","volume":"88","author":"Slavotinek","year":"2015","journal-title":"Clin. Genet."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1038\/s10038-018-0504-1","article-title":"Identification of novel pathogenic variants and novel gene-phenotype correlations in Mexican subjects with microphthalmia and\/or anophthalmia by next-generation sequencing","volume":"63","author":"Villarroel","year":"2018","journal-title":"J. Hum. Genet."},{"key":"ref_83","first-page":"1231","article-title":"Endothelial Cell Metabolism in Normal and Diseased Vasculature","volume":"116","author":"Burgess","year":"2016","journal-title":"Circ. Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/gim.2013.92","article-title":"ACMG clinical laboratory standards for next-generation sequencing","volume":"15","author":"Rehm","year":"2013","journal-title":"Genet. Med."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/1\/65\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:07:31Z","timestamp":1760159251000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/1\/65"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,6]]},"references-count":84,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["genes12010065"],"URL":"https:\/\/doi.org\/10.3390\/genes12010065","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,6]]}}}