A method for determining haploid and triploid genotypes and their association with vascular phenotypes in Williams syndrome and 7q11.23 duplication syndrome

Michael D Gregory,Karen F Berman,Carolyn B Mervis,Bhaskar Kolachana,Tiffany Nash,Dwight Dickinson,Daniel P Eisenberg,Yin Yao

doi:10.1186/s12881-018-0563-3

Abstract

BackgroundWilliams syndrome ([WS], 7q11.23 hemideletion) and 7q11.23 duplication syndrome (Dup7) show contrasting syndromic symptoms. However, within each group there is considerable interindividual variability in the degree to which these phenotypes are expressed. Though software exists to identify areas of copy number variation (CNV) from commonly-available SNP-chip data, this software does not provide non-diploid genotypes in CNV regions. Here, we describe a method for identifying haploid and triploid genotypes in CNV regions, and then, as a proof-of-concept for applying this information to explain clinical variability, we test for genotype-phenotype associations.MethodsBlood samples for 25 individuals with WS and 13 individuals with Dup7 were genotyped with Illumina-HumanOmni5M SNP-chips. PennCNV and in-house code were used to make genotype calls for each SNP in the 7q11.23 locus. We tested for association between the presence of aortic arteriopathy and genotypes of the remaining (haploid in WS) or duplicated (triploid in Dup7) alleles.ResultsHaploid calls in the 7q11.23 region were made for 99.0% of SNPs in the WS group, and triploid calls for 98.8% of SNPs in those with Dup7. The G allele of SNP rs2528795 in the ELN gene was associated with aortic stenosis in WS participants (p < 0.0049) while the A allele of the same SNP was associated with aortic dilation in Dup7.ConclusionsCommonly available SNP-chip information can be used to make haploid and triploid calls in individuals with CNVs and then to relate variability in specific genes to variability in syndromic phenotypes, as demonstrated here using aortic arteriopathy. This work sets the stage for similar genotype-phenotype analyses in CNVs where phenotypes may be more complex and/or where there is less information about genetic mechanisms.

Highlights

Williams syndrome ([WS], 7q11.23 hemideletion) and 7q11.23 duplication syndrome (Dup7) show contrasting syndromic symptoms
Start and stop locations for deletions in this locus were nearly identical across people with WS, consistent with prior literature showing stereotyped deletions in nearly 95% of people with WS [14]. Duplications in this locus were identified for all individuals with known Dup7, variability in the endpoints was slightly greater than in WS
Using B-allele frequency (BAF) thresholds (Fig. 2), haploid calls were made for 99.0% of SNPs in participants with WS (38,105/38500) and triploid calls in 98.8% of SNPs in participants with Dup7 (19,782/20020 SNPs)

Summary

Introduction

Williams syndrome ([WS], 7q11.23 hemideletion) and 7q11.23 duplication syndrome (Dup7) show contrasting syndromic symptoms. Individuals with Dup, in whom the same set of genes are duplicated [3], show the opposite pattern: impaired social functioning with high social anxiety, preserved visuospatial abilities, and speech delay or disorde [1, 3]. People with these 7q11.23 copy-number variations (CNVs) show contrasting cardiovascular abnormalities: Individuals with WS frequently have stenotic lesions, such as supravalvular aortic stenosis ([SVAS], MIM185500), which often come to clinical attention perinatally and may require surgical correction [1, 4]. Dup is associated with dilation of the ascending aorta and aortic arch [5,6,7]

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