{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T12:13:16Z","timestamp":1792843996490,"version":"4.5.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T00:00:00Z","timestamp":1695254400000},"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. Genet."],"abstract":"<jats:p>Optical genome mapping (OGM), which allows analysis of ultra-high molecular weight (UHMW) DNA molecules, represents a response to the restriction created by short-read next-generation-sequencing, even in cases where the causative variant is a neutral copy-number-variant insensitive to quantitative investigations. This study aimed to provide a molecular diagnosis to a boy with Marfan syndrome (MFS) and intellectual disability (ID) carrying a <jats:italic>de novo<\/jats:italic> translocation involving chromosomes 3, 4, and 13 and a 1.7\u00a0Mb deletion at the breakpoint of chromosome 3. No <jats:italic>FBN1<\/jats:italic> alteration explaining his Marfan phenotype was highlighted. UHMW gDNA was isolated from both the patient and his parents and processed using OGM. Genome assembly was followed by variant calling and annotation. Multiple strategies confirmed the results. The 3p deletion, which disrupted <jats:italic>ROBO2<\/jats:italic>, (MIM*602431) included three copy-neutral insertions. Two came from chromosome 13; the third contained 15q21.1, including the <jats:italic>FBN1<\/jats:italic> from intron-45 onwards, thus explaining the MFS phenotype. We could not attribute the ID to a specific gene variant nor to the reshuffling of topologically associating domains (TADs). Our patient did not have vesicular reflux-2, as reported by missense alterations of <jats:italic>ROBO2<\/jats:italic> (VUR2, MIM#610878), implying that reduced expression of all or some isoforms has a different effect than some of the point mutations. Indeed, the <jats:italic>ROBO2<\/jats:italic> expression pattern and its role as an axon-guide suggests that its partial deletion is responsible for the patient\u2019s neurological phenotype. Conclusion: OGM testing 1) highlights copy-neutral variants that could remain invisible if no loss of heterozygosity is observed and 2) is mandatory before other molecular studies in the presence of any chromosomal rearrangement for an accurate genotype-phenotype relationship.<\/jats:p>","DOI":"10.3389\/fgene.2023.1244983","type":"journal-article","created":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T13:05:36Z","timestamp":1695301536000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Case Report: Decrypting an interchromosomal insertion associated with Marfan\u2019s syndrome: how optical genome mapping emphasizes the morbid burden of copy-neutral variants"],"prefix":"10.3389","volume":"14","author":[{"given":"Maria Clara","family":"Bonaglia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliana","family":"Salvo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Sironi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Bertuzzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Errichiello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Mattina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orsetta","family":"Zuffardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.atherosclerosis.2013.12.009","article-title":"Homozygosity for a partial deletion of apoprotein A-V signal peptide results in intracellular missorting of the protein and chylomicronemia in a breast-fed infant","volume":"233","author":"Albers","year":"2014","journal-title":"Atherosclerosis"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1002\/ajmg.b.30697","article-title":"Genetic analyses of roundabout (ROBO) axon guidance receptors in autism","author":"Anitha","year":"2008","journal-title":"Am. 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