Abstract
BackgroundCornelia de Lange syndrome (CdLS) and Rubinstein-Taybi syndrome (RSTS) are both rare congenital multiple malformation disorders caused by genes associated with transcription. They share a number of similar features clinically. In addition, it is difficult to make a molecular diagnosis rapidly and detect the mosaic mutation when only sanger sequencing is taken. This study aims to report three novel mutations in three Chinese children identified by next generation sequencing.ResultsWe describe patient 1 and patient 2 presenting with characteristics of CdLS with mutations in NIPBL and patient 3 with a frame shift mutation in CREBBP who can be diagnosed as RSTS clinically and also have similar symptoms with CdLS to some extent. The splicing site c.4321-1G > A transversion in NIPBL is a mosaic mutation and produces an abnormal transcript bearing the loss of exon 20. The nonsense mutation c.218C > A in NIPBL and the frame shift c.1715delC mutation in CREBBP generate stop codon and yield the premature termination of proteins.ConclusionsIn general, we detect three novel heterozygous mutations including a splicing mutation and a nonsense mutation in NIPBL and a frame shift in CREBBP. And several similar features observed in patients indicate the clinical complexity and clinically overlapping of CdLS and RSTS termed “transcriptomopathies”, suggest the underlying molecular mechanism and emphasize the utilization of next generation sequencing technologies.
Highlights
Cornelia de Lange syndrome (CdLS) and Rubinstein-Taybi syndrome (RSTS) are both rare congenital multiple malformation disorders caused by genes associated with transcription
Five genes are responsible for CdLS: NIPBL, SMC1A, SMC3, RAD21 and HDAC8, all encoding constituents of cohesion complex or its associated regulators
Patient 1 (P1) with the A > G transition locating at c.4321 in NIPBL had typical facial abnormity of CdLS and bore light malformation in hands performing as curved 5th finger and partial webbing between 4th and 5th fingers
Summary
Cornelia de Lange syndrome (CdLS) and Rubinstein-Taybi syndrome (RSTS) are both rare congenital multiple malformation disorders caused by genes associated with transcription. They share a number of similar features clinically. Negative results in patients are probably due to somatic mosaicism, new unknown pathogenic genes or overlapping with other diseases To this day, individuals presenting with CdLS or CdLS-overlapping phenotypes have been reported and detected with causative mutations in chromatin-associated factors like AFF4, ANKRD11, KMT2A and BRD4 [16,17,18,19]. BRD4 encodes a bromodomain protein which binds to cycle-dependent kinase 9 (CDK9) and super-enhancers to regulate transcriptional elongation [22, 23] and may interacts with NIPBL and the core cohesin ring in super-enhancer function [19]
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