Recurrence and Familial Inheritance of Intronic NIPBL Pathogenic Variant Associated With Mild CdLS

Splicing pathogenic variants account for a notable fraction of alterations underlying Cornelia de Lange syndrome but are likely underrepresented, due to overlooking of non-canonical intronic variants by traditional and contemporary sequencing methods. We describe five subjects, belonging to three fa...

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Bibliographic Details
Published in:Frontiers in neurology 2018-11, Vol.9, p.967
Main Authors: Masciadri, Maura, Ficcadenti, Anna, Milani, Donatella, Cogliati, Francesca, Divizia, Maria Teresa, Larizza, Lidia, Russo, Silvia
Format: Article
Language:English
Subjects:
Cornelia de Lange
familial inheritance
intronic variant
mild phenotype
Neurology
recurrent variant
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Summary:Splicing pathogenic variants account for a notable fraction of alterations underlying Cornelia de Lange syndrome but are likely underrepresented, due to overlooking of non-canonical intronic variants by traditional and contemporary sequencing methods. We describe five subjects, belonging to three families, displaying a mild Cornelia de Lange syndrome phenotype who carry the pathogenic variant c.5329-15A>G, affecting the IVS27 branch site, yet reported in a single case. By RNA analysis we evidenced two alternative transcripts: the exon 28 in frame skipped transcript, described in the published case and an out-of-frame transcript retaining 14 nucleotides of IVS27 3'end. Even if both aberrant transcripts are at negligible levels, their presence justifies the CdLS phenotype shared by our patients consisting of borderline-mild cognitive impairment and slight but typical facial dysmorphisms. Transmission of the pathogenic variant from pauci-symptomatic mother to her siblings emphasizes the need of molecular diagnosis extended to deep intronic regions in patients with subtle but recognizable CdLS phenotype.
ISSN:1664-2295
1664-2295
DOI:10.3389/fneur.2018.00967