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

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Abstract

Splicing pathogenic variants account for a notable fraction of NIPBL 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 NIPBL 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.
Original languageItalian
JournalFrontiers in Neurology
Volume9
DOIs
Publication statusPublished - 2018

Cite this

@article{ea012ec0acde4f7d9aad9531765bd676,
title = "Recurrence and Familial Inheritance of Intronic NIPBL Pathogenic Variant Associated With Mild CdLS",
abstract = "Splicing pathogenic variants account for a notable fraction of NIPBL 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 NIPBL 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.",
author = "Maura Masciadri and Anna Ficcadenti and Donatella Milani and Francesca Cogliati and Divizia, {Maria Teresa} and Lidia Larizza and Silvia Russo",
year = "2018",
doi = "10.3389/fneur.2018.00967",
language = "Italian",
volume = "9",
journal = "Frontiers in Neurology",
issn = "1664-2295",
publisher = "Frontiers Research Foundation",

}

TY - JOUR

T1 - Recurrence and Familial Inheritance of Intronic NIPBL Pathogenic Variant Associated With Mild CdLS

AU - Masciadri, Maura

AU - Ficcadenti, Anna

AU - Milani, Donatella

AU - Cogliati, Francesca

AU - Divizia, Maria Teresa

AU - Larizza, Lidia

AU - Russo, Silvia

PY - 2018

Y1 - 2018

N2 - Splicing pathogenic variants account for a notable fraction of NIPBL 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 NIPBL 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.

AB - Splicing pathogenic variants account for a notable fraction of NIPBL 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 NIPBL 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.

U2 - 10.3389/fneur.2018.00967

DO - 10.3389/fneur.2018.00967

M3 - Articolo

VL - 9

JO - Frontiers in Neurology

JF - Frontiers in Neurology

SN - 1664-2295

ER -