dc.contributor.author | Berland, Siren | |
dc.contributor.author | Haukanes, Bjørn Ivar | |
dc.contributor.author | Juliusson, Petur Benedikt | |
dc.contributor.author | Houge, Gunnar | |
dc.date.accessioned | 2022-10-13T07:17:31Z | |
dc.date.available | 2022-10-13T07:17:31Z | |
dc.date.created | 2020-09-15T12:41:34Z | |
dc.date.issued | 2022 | |
dc.identifier.issn | 0022-2593 | |
dc.identifier.uri | https://hdl.handle.net/11250/3025751 | |
dc.description.abstract | Background: Loss-of-function mutations in CDKN1C cause overgrowth, that is, Beckwith-Wiedemann syndrome (BWS), while gain-of-function variants in the gene’s PCNA binding motif cause a growth-restricted condition called IMAGe syndrome. We report on a boy with a remarkable mixture of both syndromes, with developmental delay and microcephaly as additional features.
Methods: Whole-exome DNA sequencing and ultra-deep RNA sequencing of leucocyte-derived and fibroblast-derived mRNA were performed in the family.
Results: We found a maternally inherited variant in the IMAGe hotspot region: NM_000076.2(CDKN1C) c.822_826delinsGAGCTG. The asymptomatic mother had inherited this variant from her mosaic father with mild BWS features. This delins caused tissue-specific frameshifting resulting in at least three novel mRNA transcripts in the boy. First, a splice product causing CDKN1C truncation was the likely cause of BWS. Second, an alternative splice product in fibroblasts encoded IMAGe-associated amino acid substitutions. Third, we speculate that developmental delay is caused by a change in the alternative CDKN1C-201 (ENST00000380725.1) transcript, encoding a novel isoform we call D (UniProtKB: A6NK88). Isoform D is distinguished from isoforms A and B by alternative splicing within exon 1 that changes the reading frame of the last coding exon. Remarkably, this delins changed the reading frame back to the isoform A/B type, resulting in a hybrid D–A/B isoform.
Conclusion: Three different cell-type-dependent RNA products can explain the co-occurrence of both BWS and IMAGe features in the boy. Possibly, brain expression of hybrid isoform D–A/B is the cause of developmental delay and microcephaly, a phenotypic feature not previously reported in CDKN1C patients. | en_US |
dc.language.iso | eng | en_US |
dc.publisher | BMJ | en_US |
dc.rights | Navngivelse-Ikkekommersiell 4.0 Internasjonal | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc/4.0/deed.no | * |
dc.title | Deep exploration of a CDKN1C mutation causing a mixture of Beckwith-Wiedemann and IMAGe syndromes revealed a novel transcript associated with developmental delay | en_US |
dc.type | Journal article | en_US |
dc.type | Peer reviewed | en_US |
dc.description.version | publishedVersion | en_US |
dc.rights.holder | Copyright 2022 the authors | en_US |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 2 | |
dc.identifier.doi | 10.1136/jmedgenet-2020-107401 | |
dc.identifier.cristin | 1830051 | |
dc.source.journal | Journal of Medical Genetics | en_US |
dc.source.pagenumber | 155-164 | en_US |
dc.identifier.citation | Journal of Medical Genetics. 2022, 59 (2), 155-164. | en_US |
dc.source.volume | 59 | en_US |
dc.source.issue | 2 | en_US |