Deep exploration of a CDKN1C mutation causing a mixture of Beckwith-Wiedemann and IMAGe syndromes revealed a novel transcript associated with developmental delay

We present a child with an unexpected combination of both Beckwith-Wiedemann syndrome (BWS), an imprinted overgrowth condition, and IMAGe syndrome, a growth-restricted condition. The child also has developmental delay and microcephaly, apparently unrelated features. However, all features can potentially be explained by a single CDKN1C delins mutation, de novo mosaic in the maternal grandfather, due to complex splicing. Differential splicing caused CDKN1C loss-of-function explaining BWS, gain-of-function explaining IMAGe, and potential change-of-function affecting the brain. The latter changes the C-terminus of the novel brain-abundant CDKN1C isoform D (A6NK88) to the C-terminus of isoforms A and B, creating a hybrid D-A/B protein. (By Dr. Siren Berland, https://jmg.bmj.com/content/early/2020/12/20/jmedgenet-2020-107401 )

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