TY - JOUR AU - Masciadri, Maura AU - Ficcadenti, Anna AU - Milani, Donatella AU - Cogliati, Francesca AU - Divizia, Maria Teresa AU - Larizza, Lidia AU - Russo, Silvia PY - 2018 M3 - Case Report TI - Recurrence and Familial Inheritance of Intronic NIPBL Pathogenic Variant Associated With Mild CdLS JO - Frontiers in Neurology UR - https://www.frontiersin.org/articles/10.3389/fneur.2018.00967 VL - 9 SN - 1664-2295 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. ER -