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

Abstract

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.

Case report: A novel heterozygous synonymous variant in deep exon region of NIPBL gene generating a non-canonical splice donor in a patient with cornelia de lange syndrome

“…However, accumulating evidence has shown that some specific synonymous variations can lead to diseases by influencing the mRNA stability and alternative splicing of exons ( Nackley et al, 2006 ; Sauna and Kimchi-Sarfaty, 2011 ), which should garner more interest. To date, only one fetal case with a NIPBL synonymous variant has been reported, providing limited phenotypic information related to a specific variant ( Qiao et al, 2021 ). This is presumably a result of the difficulty in recognizing fetal features in utero or the late onset of clinical manifestations, which do not appear during the early developmental stage.…”

“…Most variants in these typical loci can change the splicing of exons and introns, resulting in specific diseases. Hence, to a large extent, they are unlikely to be ignored in routine analysis, as in the previously reported CdLS case with a synonymous variant at the last base of exon 27 in the NIPBL gene ( Qiao et al, 2021 ). Diseases caused by synonymous variations in deep exonic or introns are uncommon.…”

“…However, little is known about these rare disease-causing variations, especially synonymous variants. To date, only one synonymous NIPBL variant has been reported in a fetal case ( Qiao et al, 2021 ). Few recognizable features were observed during the prenatal stage in the patient carrying a synonymous variant, and only skeletal dysplasia of the bilateral upper extremity and congenital heart defects were observed in the fetus ( Qiao et al, 2021 ).…”

“…To date, only one synonymous NIPBL variant has been reported in a fetal case ( Qiao et al, 2021 ). Few recognizable features were observed during the prenatal stage in the patient carrying a synonymous variant, and only skeletal dysplasia of the bilateral upper extremity and congenital heart defects were observed in the fetus ( Qiao et al, 2021 ). Thus, synonymous variants in NIPBL and their genotype-phenotype correlation with CdLS remain unelucidated.…”

Early Prenatal Diagnosis of Cornelia de Lange's Syndrome with Whole-Exome Sequencing: A Case Report

“…In 2019, a prospective study on use of WES for fetal structural anomalies demonstrated an additional diagnostic rate of 30% in fetuses with three (3) or more anomalies above routine chromosomal microarray. 9 The benefits of providing a definitive genetic diagnosis of ultrasound abnormalities are self-evident in terms of improved decision-making for pregnancy management, reproductive decision-making for current and future pregnancies, recurrence risk, and testing options.…”