De novo NIPBL Mutations in Vietnamese Patients with Cornelia de Lange Syndrome

Abstract

Cornelia de Lange Syndrome (CdLS) is a rare congenital genetic disease causing abnormal unique facial phenotypes, several defects in organs and body parts, and mental disorder or intellectual disorder traits. Main causes of CdLS have been reported as variants in cohesin complex genes, in which mutations in the NIPBL gene have been estimated to account for up to 80%. Our study included three Vietnamese patients with typical CdLS phenotypes. Whole exome sequencing revealed two known heterozygous mutations c.6697G>A (p.Val2233Met) and c.2602C>T (p.Arg868X), and a novel heterozygous mutation c.4504delG (p.Val1502fsX87) in the NIPBL gene of the three patients. In silico analyses of the identified mutations predicted possible damaging and truncating effects on the NIPBL protein. Inherited analyses in the patients' families showed that all of the mutations are de novo. Our results lead a definitive diagnosis of patients with CdLS and expand the spectrum of mutations in the NIPBL gene. These findings also confirm whole exome sequencing is an efficient tool for genetic screening of CdLS.

Activation-induced chromatin reorganization in neurons depends on HDAC1 activity

“…One of the possible HDAC1 targets are cohesins, as their activity is necessary for chromatin condensation (Makrantoni and Marston, 2018). Several lines of evidence connect deacetylases with cohesins (Borges et al, 2010;Jahnke al., 2008;Thanh et al, 2020), a ring-like protein complex that can ultimately bring together two DNA segments from different locations. By a mechanism of ATP-dependent loop extrusion, cohesin promotes chromatin looping and plays a central role in the organization of the higher-order chromatin structure of mammalian genomes (Schwarzer et al, 2017).…”

Cerebellar Hypoperfusion in Two Patients with Cornelia de Lange Syndrome with Novel NIPBL Variants

“…The variants associated with CdLS are widely distributed in the whole NIPBL gene. In particular, many variants located in exon 10 have been associated with CdLS, including our patient 2, because exon 10 is approximately 8 times larger than the average exon in the NIPBL gene [Thanh et al, 2020]. In patient 2, a 101-bp insertion between c.1751 and c.1752 was identified, the sequence of which was exactly the same as the reference sequence from c.1652 to c.1751 just upstream from the insertion, with the exception of the first inserted adenine.…”