Identification of two novel heterozygous variants of SMC3 with Cornelia de Lange syndrome

Author:

Lei Zhi1ORCID,Song Xiaorui1,Zheng Xuan1,Wang Yanhong1,Wang Yingyuan2,Wu Zhirong3,Fan Tian2,Dong Shijie4,Cao Honghui5,Zhao Yuefang6,Xia Zhiyi1,Gao Liujiong7,Shang Qing3,Mei Shiyue1ORCID

Affiliation:

1. Henan Key Laboratory of Children's Genetics and Metabolic Diseases Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou Henan China

2. Department of Neonatal Medicine Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou Henan China

3. Rehabilitation Center Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou Henan China

4. Department of Medical Imaging Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou Henan China

5. Department of Ophthalmology Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou Henan China

6. School of Life Sciences Inner Mongolia University Hohhot Inner Mongolia China

7. Department of Pediatric Intensive Care Unit Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou Henan China

Abstract

AbstractBackgroundCornelia 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.MethodsClinical 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.ResultsNovel 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.ConclusionBoth 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.

Funder

Natural Science Foundation of Henan Province

National Natural Science Foundation of China

Publisher

Wiley

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