{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T06:02:47Z","timestamp":1780293767209,"version":"3.54.0"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      <jats:italic>COG5<\/jats:italic>\n                      -related congenital disorder of glycosylation (COG5-CDG) is a rare autosomal recessive metabolic disorder with variable neurologic and ophthalmologic involvement. We report two siblings presenting with optic atrophy, macular atrophy, and neurodevelopmental delay; these three phenotypic manifestations have not, to our knowledge, been combined together in previously described individuals with COG5-CDG. The genetic disorder was only diagnosed through whole genome sequencing (WGS) after panel-based exome testing was unrevealing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical findings<\/jats:title>\n                    <jats:p>Both siblings presented with early-onset severe visual impairment, bilateral optic atrophy, central macular atrophy, sensory nystagmus, and strabismus in the setting of global developmental delay. Additional features included polymicrogyria and hypotonia (Case 1) and microcephaly and autism spectrum disorder (Case 2).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Diagnoses and outcomes<\/jats:title>\n                    <jats:p>\n                      After repeated non-diagnostic inherited retinal gene panels, clinical quad WGS identified compound heterozygous variants in\n                      <jats:italic>COG5<\/jats:italic>\n                      in both siblings: a paternally inherited pathogenic frameshift variant (c.1415dup) and a maternally inherited deep intronic variant (c.417\u202f+\u202f4779A&amp;gt;G) with high SpliceAI-predicted splicing impact. Visual function has remained relatively stable over 5\u202fyears of follow-up.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These cases expand the phenotypic spectrum of COG5-CDG to include concurrent optic nerve and macular involvement with neurodevelopmental impairment and highlight the essential role of WGS in diagnosing complex neuro-ophthalmologic presentations when targeted genetic testing is nondiagnostic.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1840802","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T05:28:42Z","timestamp":1780291722000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["COG5-congenital disorder of glycosylation diagnosed by whole genome sequencing in siblings with unexplained optic atrophy, macular atrophy, and developmental delay: case report"],"prefix":"10.3389","volume":"17","author":[{"given":"Katherine","family":"Granger","sequence":"first","affiliation":[{"name":"Department of Surgery, Vision Center, Children\u2019s Hospital Los Angeles","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Do","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Quindipan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Hospital Los Angeles","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Hospital Los Angeles","place":["Los Angeles, CA, United States"]},{"name":"Department of Pathology, Keck School of Medicine, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark S.","family":"Borchert","sequence":"additional","affiliation":[{"name":"Department of Surgery, Vision Center, Children\u2019s Hospital Los Angeles","place":["Los Angeles, CA, United States"]},{"name":"Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Nagiel","sequence":"additional","affiliation":[{"name":"Department of Surgery, Vision Center, Children\u2019s Hospital Los Angeles","place":["Los Angeles, CA, United States"]},{"name":"Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melinda Y.","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Vision Center, Children\u2019s Hospital Los Angeles","place":["Los Angeles, CA, United States"]},{"name":"Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"477","DOI":"10.21037\/atm.2018.10.45","article-title":"Congenital disorders of glycosylation","volume":"6","author":"Chang","year":"2018","journal-title":"Ann Transl Med"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1007\/s10545-017-0050-6","article-title":"What is new in CDG?","volume":"40","author":"Jaeken","year":"2017","journal-title":"J Inherit Metab Dis"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/S1474-4422(12)70040-6","article-title":"Neurology of inherited glycosylation disorders","volume":"11","author":"Freeze","year":"2012","journal-title":"Lancet Neurol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.tcb.2005.12.004","article-title":"Retrograde transport on the COG railway","volume":"16","author":"Ungar","year":"2006","journal-title":"Trends Cell Biol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2466","DOI":"10.1002\/1873-3468.13570","article-title":"Maintaining order: COG complex controls Golgi trafficking, processing, and sorting","volume":"593","author":"Blackburn","year":"2019","journal-title":"FEBS Lett"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"3244","DOI":"10.1093\/hmg\/ddp262","article-title":"Golgi function and dysfunction in the first COG4-deficient CDG type II patient","volume":"18","author":"Reynders","year":"2009","journal-title":"Hum Mol Genet"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1186\/1750-1172-7-94","article-title":"COG5-CDG: expanding the clinical spectrum","volume":"7","author":"Rymen","year":"2012","journal-title":"Orphanet J Rare Dis"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"4350","DOI":"10.1093\/hmg\/ddp389","article-title":"Deficiency in COG5 causes a moderate form of congenital disorders of glycosylation","volume":"18","author":"Paesold-Burda","year":"2009","journal-title":"Hum Mol Genet"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"168","DOI":"10.3389\/fgene.2020.00168","article-title":"Identification of two novel mutations in COG5 causing congenital disorder of glycosylation","volume":"11","author":"Wang","year":"2020","journal-title":"Front Genet"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"21269","DOI":"10.1038\/s41598-020-77394-3","article-title":"COG5 variants lead to complex early onset retinal degeneration, upregulation of PERK and DNA damage","volume":"10","author":"Tabbarah","year":"2020","journal-title":"Sci Rep"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"101072","DOI":"10.1016\/j.ymgmr.2024.101072","article-title":"Novel mutation of COG5 in a Taiwanese girl with congenital disorders of glycosylation manifesting as developmental delay","volume":"39","author":"Wang","year":"2024","journal-title":"Mol Genet Metab Rep"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/0039-6257(94)90155-4","article-title":"Congenital optic disk anomalies","volume":"39","author":"Brodsky","year":"1994","journal-title":"Surv Ophthalmol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1111\/cge.13102","article-title":"Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of 2 clinical units and 216 patients","volume":"93","author":"Ch\u00e9rot","year":"2018","journal-title":"Clin Genet"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/s41525-018-0053-8","article-title":"Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases","volume":"3","author":"Clark","year":"2018","journal-title":"NPJ Genom Med"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1038\/gim.2014.154","article-title":"Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions","volume":"17","author":"Farwell","year":"2015","journal-title":"Genet Med"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"2131","DOI":"10.1056\/NEJMoa1714458","article-title":"Effect of genetic diagnosis on patients with previously undiagnosed disease","volume":"379","author":"Splinter","year":"2018","journal-title":"N Engl J Med"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"100995","DOI":"10.1016\/j.gim.2023.100995","article-title":"Evidence from 2100 index cases supports genome sequencing as a first-tier genetic test","volume":"26","author":"Guo","year":"2024","journal-title":"Genet Med"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/s41431-022-01185-9","article-title":"The performance of genome sequencing as a first-tier test for neurodevelopmental disorders","volume":"31","author":"van der Sanden","year":"2023","journal-title":"Eur J Hum Genet"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"ACMG laboratory quality assurance committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41586-023-06045-0","article-title":"A genomic mutational constraint map using variation in 76,156 human genomes","volume":"625","author":"Chen","year":"2024","journal-title":"Nature"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting splicing from primary sequence with deep learning","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1007\/s00439-017-1809-4","article-title":"Deep intronic mutations and human disease","volume":"136","author":"Vaz-Drago","year":"2017","journal-title":"Hum Genet"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.1093\/brain\/aws019","article-title":"A developmental and genetic classification for malformations of cortical development: update 2012","volume":"135","author":"Barkovich","year":"2012","journal-title":"Brain"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1016\/S1474-4422(14)70040-7","article-title":"Malformations of cortical development: clinical features and genetic causes","volume":"13","author":"Guerrini","year":"2014","journal-title":"Lancet Neurol"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1840802\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T05:28:45Z","timestamp":1780291725000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1840802\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,1]]},"references-count":24,"alternative-id":["10.3389\/fneur.2026.1840802"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2026.1840802","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,1]]},"article-number":"1840802"}}