TY - JOUR
T1 - Recurrence and Familial Inheritance of Intronic NIPBL Pathogenic Variant Associated with Mild CdLSs
AU - Masciadri, Maura
AU - Ficcadenti, Anna
AU - Milani, Donatella
AU - Cogliati, Francesca
AU - Divizia, Maria Teresa
AU - Larizza, Lidia
AU - Russo, Silvia
PY - 2018/11/27
Y1 - 2018/11/27
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.
KW - Cornelia de Lange
KW - Familial inheritance
KW - Intronic variant
KW - Mild phenotype
KW - Recurrent variant
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U2 - 10.3389/fneur.2018.00967
DO - 10.3389/fneur.2018.00967
M3 - Article
AN - SCOPUS:85057822212
VL - 9
JO - Frontiers in Neurology
JF - Frontiers in Neurology
SN - 1664-2295
IS - NOV
M1 - 967
ER -