Journal
HUMAN MUTATION
Volume 43, Issue 9, Pages 1239-1248Publisher
WILEY-HINDAWI
DOI: 10.1002/humu.24384
Keywords
5 '-UTR; cornelia de lange syndrome; de novo mutation; neurodevelopmental disorder; uORF
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Funding
- European Regional Development Fund
- Recherche Innovation Normandie [RIN2018]
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Cornelia de Lange syndrome (CdLS) is a rare developmental disorder. This study identified variants in the 5'-untranslated region (UTR) of the NIPBL gene that may introduce an upstream open reading frame (uORF), leading to loss of function. The results suggest that uORF-introducing NIPBL variants may be a rare source of pathogenic variants in unsolved CdLS patients.
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.
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