A New Mutation Identified by Whole Exome Sequencing in a Cornelia de Lange Syndrome Newborn

Background: Cornelia de Lange Syndrome (CdLS) is a rare but severe clinically heterogeneous developmental disorder characterized by facial dysmorphia, growth and cognitive retardation, and abnormalities of limb development. Objectives: To determine the pathogenesis of a patient with CdLS. Methods: We studied a patient with CdLS by whole exome sequencing, karyotyping and Agilent CGH Array. The results were confirmed by quantitative real-time PCR analysis of the patient and her parents. Further comparison of our patient and cases with partially overlapping deletions retrieved from the literature and databases was undertaken. Results: Whole exome sequencing had excluded the mutation of cohesion genes such as NIPBL,SMC1A and SMC3. The result of karyotyping showed a deletion of chromosome 9q31.1-q32 and the result of Agilent CGH Array further displayed a 12.01-Mb region of deletion at chromosome bands 9q31.1-q32. Reported cases with the deletion of 9q31.1-q32 share similar features with our CdLS patient. One of the genes in the deleted region, SMC2, belongs to the Structural Maintenance of Chromosomes (SMC) family and regulates gene expression and DNA repair. Conclusions: Patients carrying the deletion of 9q31.1-q32 showed similar phenotypes with CdLS.

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Case Report: Prenatal Whole-Exome Sequencing to Identify a Novel Heterozygous Synonymous Variant in NIPBL in a Fetus With Cornelia de Lange Syndrome

Frontiers in Genetics ◽

10.3389/fgene.2021.628890 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fengchang Qiao ◽

Cuiping Zhang ◽

Yan Wang ◽

Gang Liu ◽

Binbin Shao ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

De Novo ◽

Cornelia De Lange Syndrome ◽

Splice Donor Site ◽

Synonymous Mutations ◽

Craniofacial Dysmorphism ◽

Whole Exome ◽

Synonymous Variant ◽

Cornelia De Lange

Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder characterized by a wide spectrum of abnormalities, including craniofacial dysmorphism, upper limb anomalies, pre- and post-natal growth restrictions, hirsutism and intellectual disability. Approximately 60% of cases are caused by NIPBL variants. Herein we report on a prenatal case presented with bilateral upper-extremity malformations and cardiac defects. Whole-exome sequencing (WES) was performed on the fetus–parental trio and a de novo heterozygous synonymous variant in NIPBL [chr5:37020979; NM_133433.4: c.5328G>A, p. (Gln1776=)] was identified. Reverse transcriptase–polymerase chain reaction (RT–PCR) was conducted to evaluate the potential splicing effect of this variant, which confirmed that the variant caused a deletion of exon 27 (103 bp) by disrupting the splice-donor site and changed the reading frame with the insertion of at least three stop codons. Our finding not only expands the mutation spectrum of NIPBL gene but also establishes the crucial role of WES in searching for underlying genetic variants. In addition, our research raises the important issue that synonymous mutations may be potential pathogenic variants and should not be neglected in clinical diagnoses.

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

Medicina ◽

10.3390/medicina56020076 ◽

2020 ◽

Vol 56 (2) ◽

pp. 76

Author(s):

Duong Chi Thanh ◽

Can Thi Bich Ngoc ◽

Ngoc-Lan Nguyen ◽

Chi Dung Vu ◽

Nguyen Van Tung ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

De Novo ◽

Cornelia De Lange Syndrome ◽

Heterozygous Mutation ◽

Body Parts ◽

Efficient Tool ◽

Whole Exome ◽

Cornelia De Lange ◽

In Silico Analyses

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.

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