LAUSR

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.