%0 Journal Article
%T Identification of two novel heterozygous variants of SMC3 with Cornelia de Lange syndrome.
%A Lei Z
%A Song X
%A Zheng X
%A Wang Y
%A Wang Y
%A Wu Z
%A Fan T
%A Dong S
%A Cao H
%A Zhao Y
%A Xia Z
%A Gao L
%A Shang Q
%A Mei S
%J Mol Genet Genomic Med
%V 12
%N 5
%D 2024 May
%M 38733165
%F 2.473
%R 10.1002/mgg3.2447
%X <B>BACKGROUND: </B>Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder, and cases caused by variants in the structural maintenance of chromosomes protein 3 (SMC3) gene are uncommon. Here, we report two cases of CdLS associated with novel pathogenic variants in SMC3 from two Chinese families.<BR><B>METHODS: </B>Clinical presentations of two patients with CdLS were evaluated, and specimens from the patients and other family members were collected for Trio-based whole-exome sequencing. Pyrosequencing, chip-based digital PCR, minigene splicing assay, and in silico analysis were carried out to elucidate the impact of novel variants.<BR><B>RESULTS: </B>Novel heterozygous variants in SMC3 were identified in each proband. One harbored a novel splicing and mosaic variant (c.2535+1G>A) in SMC3. The mutated allele G>A conversion was approximately 23.1% by digital PCR, which indicated that 46.2% of peripheral blood cells had this variant. Additionally, in vitro minigene splicing analysis validated that the c.2535+1G>A variant led to an exon skipping in messenger RNA splicing. The other carried a heterozygous variant (c.435C>A), which was predicted to be pathogenic as well as significantly altered in local electrical potential. The former showed multiple abnormalities and marked clinical severity, and the latter mainly exhibited a speech developmental disorder and slightly facial anomalies.<BR><B>CONCLUSIONS: </B>Both patients were clinically diagnosed with Cornelia de Lange syndrome 3 (CdLS3). The newly identified SMC3 gene variants can expand the understanding of CdLS3 and provide reliable evidence for genetic counseling to the affected family.