{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T18:14:58Z","timestamp":1791396898825,"version":"4.3.3"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T00:00:00Z","timestamp":1742947200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006005","name":"Agence de la Biom\u00e9decine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Nucleotide excision repair (NER) disorders are genetic conditions caused by defects in the pathway responsible for repairing DNA lesions due to UV radiation. These defects lead to a variety of heterogeneous disorders, including Cockayne syndrome (CS) and trichothiodystrophy (TTD). In this study, we report 11 patients initially suspected of having CS or TTD who were ultimately diagnosed with <jats:italic>DYRK1A<\/jats:italic> haploinsufficiency syndrome using high-throughput sequencing. Comparing clinical presentations, we observed that <jats:italic>DYRK1A<\/jats:italic> symptoms overlapped with CS, with shared features such as intellectual disability and microcephaly, systematically present in both disorders and other common symptoms including feeding difficulties, abnormal brain imaging, ataxic gait, hypertonia, and deep-set eyes. However, distinctive features of <jats:italic>DYRK1A<\/jats:italic> syndrome, such as severely impaired language, febrile seizures, and autistic behavior or anxiety, helped differentiate it from CS, which typically manifests with severe growth delay, bilateral cataracts, and pigmentary retinopathy. Among the cohort, three patients carried novel <jats:italic>DYRK1A<\/jats:italic> variants, including two truncating and one in-frame variant p.Val237_Leu241delinsGlu whose pathogenicity have been confirmed through functional analysis of DYRK1A protein. While previous research has implicated DYRK1A in DNA repair, with <jats:italic>DYRK1A<\/jats:italic> being one of the most downregulated genes in CS cells, our study found that DYRK1A patient-derived cell lines did not exhibit NER defects and did not share the CS transcriptomic signature. These findings suggest that if clinical symptoms overlap stems from common molecular disruptions, <jats:italic>DYRK1A<\/jats:italic> is involved downstream of the CS genes. This research highlights the importance of considering <jats:italic>DYRK1A<\/jats:italic> haploinsufficiency syndrome in the differential diagnoses for NER disorders.<\/jats:p>","DOI":"10.3389\/fnins.2025.1554093","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T07:41:39Z","timestamp":1742974899000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical and molecular overlap between nucleotide excision repair (NER) disorders and DYRK1A haploinsufficiency syndrome"],"prefix":"10.3389","volume":"19","author":[{"given":"Nicolas","family":"Le May","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00e9mie","family":"Courraud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Im\u00e8ne","family":"Boujelb\u00e8ne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Obringer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoo","family":"Ogi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan R.","family":"Lehmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Laffargue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daphn\u00e9","family":"Lehalle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiji","family":"Mizuno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shehla","family":"Mohammed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clothilde","family":"Ormi\u00e8res","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjolaine","family":"Willems","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Laugel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nad\u00e8ge","family":"Calmels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,26]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1277537","DOI":"10.3389\/fcell.2023.1277537","article-title":"Insights from the protein interaction universe of the multifunctional \u201cgoldilocks\u201d kinase DYRK1A","volume":"11","author":"Ananthapadmanabhan","year":"2023","journal-title":"Front. 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Med."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/nature21062","article-title":"Prevalence and architecture of de novo mutations in developmental disorders","volume":"542","year":"2017","journal-title":"Nature"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1016\/j.molcel.2017.11.009","article-title":"Cockayne\u2019s syndrome a and B proteins regulate transcription arrest after genotoxic stress by promoting ATF3 degradation","volume":"68","author":"Epanchintsev","year":"2017","journal-title":"Mol. Cell"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1038\/s41598-020-57999-4","article-title":"Defective transcription of ATF3 responsive genes, a marker for Cockayne syndrome","volume":"10","author":"Epanchintsev","year":"2020","journal-title":"Sci. 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Genomic Med."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"234","DOI":"10.3390\/genes12020234","article-title":"Ocular phenotype associated with DYRK1A variants","volume":"12","author":"M\u00e9j\u00e9case","year":"2021","journal-title":"Genes (Basel)"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1080\/15384101.2019.1577525","article-title":"DYRK1A regulates the recruitment of 53BP1 to the sites of DNA damage in part through interaction with RNF169","volume":"18","author":"Menon","year":"2019","journal-title":"Cell Cycle"},{"key":"ref9002","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1002\/ajmg.1320420115","article-title":"Cockayne syndrome: review of 140 cases","volume":"42","author":"Nance","year":"1992","journal-title":"Am J Med Genet"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1146\/annurev-biochem-052621-091205","article-title":"Transcription-coupled nucleotide excision repair and the transcriptional response to UV-induced DNA damage","volume":"92","author":"Nieto Moreno","year":"2023","journal-title":"Annu. 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Pediatr."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1186\/s13023-021-01686-8","article-title":"Diagnostic and severity scores for Cockayne syndrome","volume":"16","author":"Spitz","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.pediatrneurol.2023.01.011","article-title":"The Spectrum of MORC2-related disorders: a potential link to Cockayne syndrome","volume":"141","author":"Stafki","year":"2023","journal-title":"Pediatr. 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