uORF‐introducing variants in the 5′UTR of the NIPBL gene as a cause of Cornelia de Lange syndrome

Juliette Coursimault (1, 2) , Anne Rovelet-Lecrux (1, 2) , Kévin Cassinari (2, 1) , Elise Brischoux-Boucher (3) , Pascale Saugier-Veber (1, 2) , Alice Goldenberg (2, 1) , François Lecoquierre (1, 2) , Nathalie Drouot (1, 2) , Anne‐claire Richard (1, 2) , Gabriella Vera (1, 2) , Sophie Coutant (1, 2) , Olivier Quenez (1, 2) , Marion Rolain (1, 2) , Céline Bonnet (4) , Myriam Bronner (5, 4) , Magalie Lecourtois (1, 2) , Gaël Nicolas (1, 2)

1 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
2 CHU Rouen
3 Centre de génétique humaine [CHRU Besançon]
4 Service de Génétique [CHRU Nancy]
5 NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux

Cornelia de Lange syndrome (CdLS) is a clinically-recognizable rare developmental disorder. About 70% of patients carry a missense or loss-of-function pathogenic variant in the NIPBL gene. We hypothesized that some variants in the 5'-untranslated region (UTR) of NIPBL may create an upstream open reading frame (uORF), putatively leading to a loss of function. We searched for NIPBL 5'-UTR variants potentially introducing uORF by (i) reannotating NGS data of 102 unsolved CdLS patients and (ii) literature and variant databases search. We set up a green fluorescent protein (GFP) reporter assay and studied NIPBL expression in a lymphoblastoid cell line (LCL). We identified two variants introducing a novel ATG codon sequence in the 5'-UTR of NIPBL, both predicted to introduce uORF: a novel c.-457_-456delinsAT de novo mutation in a 15-year-old male with classic CdLS, and a c.-94C>T variant in a published family. Our reporter assay showed a significant decrease of GFP levels in both mutant contexts, with similar levels of messenger RNA (mRNA) as compared to wt constructs. Assessment of LCL of one patient showed consistent results with decreased NIPBL protein and unchanged mRNA levels. 5'-UTR uORF-introducing NIPBL variants may represent a rare source of pathogenic variants in unsolved CdLS patients.

Mots clés: 5 '-UTR; Cornelia de lange syndrome; De novo mutation; Neurodevelopmental disorder; UORF

Domaines: Sciences du Vivant [q-bio]

Juliette Coursimault, Anne Rovelet-Lecrux, Kévin Cassinari, Elise Brischoux-Boucher, Pascale Saugier-Veber, et al.. uORF‐introducing variants in the 5′UTR of the NIPBL gene as a cause of Cornelia de Lange syndrome. Human Mutation, 2022, 43 (9), pp.1239-1248. ⟨10.1002/humu.24384⟩. ⟨hal-03822689⟩