{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T09:46:23Z","timestamp":1792143983230,"version":"4.4.0"},"reference-count":36,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:italic>PAX6<\/jats:italic>\n                    encodes a dosage\u2010sensitive transcription factor that is essential for eye development. Heterozygous\n                    <jats:italic>PAX6<\/jats:italic>\n                    disease is well characterized, but biallelic disease is extremely rare and has been associated with anophthalmia, severe brain malformations, and perinatal lethality. Here we report the first adult patient with biallelic pathogenic\n                    <jats:italic>PAX6<\/jats:italic>\n                    variants and describe a novel phenotype that includes severe microphthalmia, anosmia, and autism spectrum disorder, Level 1. Notably, intellectual function was preserved. Genome sequencing revealed compound heterozygosity for the missense variant c.622C&gt;T p.(Arg208Trp), inherited from the patient's mother diagnosed with sclerocornea and iris hypoplasia, and the nonsense variant c.718C&gt;T p.(Arg240*), inherited from the patient's father diagnosed with aniridia. We compare the phenotype and genotype with previously reported biallelic patients and observe that the neurological phenotype of the patient fits the pattern observed in\n                    <jats:italic>PAX6<\/jats:italic>\n                    haploinsufficiency. We propose that the severe microphthalmia is the result of haploinsufficiency and a hypomorphic, eye\u2010restricted effect of the missense variant, which is predicted to affect the DNA\u2010binding homeodomain of\n                    <jats:italic>PAX6<\/jats:italic>\n                    . Together, these findings expand the phenotypic spectrum of biallelic\n                    <jats:italic>PAX6<\/jats:italic>\n                    disease and suggest that the homeodomain may have a tissue\u2010specific role that is critical for eye development but largely dispensable for brain development.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70330","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T09:09:46Z","timestamp":1792141786000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biallelic\n                    <scp>\n                      <i>PAX6<\/i>\n                    <\/scp>\n                    Variants in an Adult With Severe Microphthalmia and Preserved Intellectual Function"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7849-2082","authenticated-orcid":false,"given":"Karl De","family":"Geer","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Surgery Karolinska Institutet  Stockholm Sweden"},{"name":"Department of Clinical Genetics and Genomics Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britt\u2010Marie","family":"Anderlid","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery Karolinska Institutet  Stockholm Sweden"},{"name":"Department of Clinical Genetics and Genomics Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8563-2127","authenticated-orcid":false,"given":"Lena","family":"Jacobson","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience, Section for Eye and Vision Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1038-6168","authenticated-orcid":false,"given":"Daniel Mart\u00edn","family":"Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Bj\u00f6rck","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery Karolinska Institutet  Stockholm Sweden"},{"name":"Department of Clinical Genetics and Genomics Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,16]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2019.10.011"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00815"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.11606\/s1518\u20108787.2022056004175"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2022.101133"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/159.4.1689"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0894\u2010463"},{"key":"e_1_2_12_8_1","first-page":"407","article-title":"Familial Congenital Cataract, Coloboma, and Nystagmus Phenotype With Variable Expression Caused by Mutation in PAX6 in a South African Family","volume":"24","author":"Goolam S.","year":"2018","journal-title":"Molecular Vision"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2021.147283"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0925\u20104773(97)00055\u20105"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7892602"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/2.7.915"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01524"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/354522a0"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.17.6.478"},{"key":"e_1_2_12_16_1","first-page":"95","article-title":"Small Eyes (Sey): A Homozygous Lethal Mutation on Chromosome 2 Which Affects the Differentiation of Both Lens and Nasal Placodes in the Mouse","volume":"97","author":"Hogan B. 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