Abstract
Background
Williams-Beuren syndrome (WBS) is a severe congenital disorder. Prenatal diagnosis of WBS is difficult because the phenotypes of WBS fetuses are atypical or incomplete. This study used ultrasound, SNP array, and whole exome sequencing to analyze the association between genotype and complex phenotype in fetuses with WBS.
Methods
Chromosomal microarray analysis (CMA) and whole genome sequencing were performed in pregnant women with prenatal diagnosis. Genome-wide copy number variants (CNVs), regions of homozygosity (ROH), single nucleotide variants (SNVs), small insertions and deletions, and splice sites were analyzed.
Results
The 7q11.23 deletion was identified in seven fetuses out of 6718 prenatal diagnostic samples; ultrasound revealed that two fetuses had apparent cardiovascular anomalies; one fetus had persistent left superior vena cava and intrauterine growth retardation (IUGR). Two fetuses had polycystic kidney dysplasia, one of which was associated with a small amount of tricuspid regurgitation; the other two fetuses had no apparent ultrasound abnormalities. Detailed genetic analysis revealed CNVs ranging in size from 1.43 megabase pairs (Mb) to 1.66 Mb, affecting 34 to 41 genes, respectively. On average, 1.0 additional CNVs larger than 100 kilobase pairs of unknown significance and 0.43 ROH larger than 5 Mb were detected in these cases. The pathogenic or likely pathogenic SNV or splice site with the function of renal development and cardiovascular development was also identified in these cases.
Conclusion
The phenotype of WBS fetuses is atypical and complex, and the complex phenotype does not exclude association with other variants within the genome.