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BMC Med Genet. 2018 Apr 4;19(1):53. doi: 10.1186/s12881-018-0563-3.

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

Author information

1
Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive 3C-216, Bethesda, MD, 20892, USA. gregorymd@mail.nih.gov.
2
Human Brain Collection Core, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
3
Statistical Genomics Core, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
4
Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive 3C-216, Bethesda, MD, 20892, USA.
5
Neurodevelopmental Sciences Laboratory, Department of Psychological & Brain Sciences, University of Louisville, Louisville, KY, USA.

Abstract

BACKGROUND:

Williams 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.

METHODS:

Blood 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.

RESULTS:

Haploid 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.

CONCLUSIONS:

Commonly 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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01132885.

KEYWORDS:

Aortic dilation; CNV; Dup7; Elastin; Genotype-phenotype association; Haploid; PennCNV; SVAS; Triploid; Williams syndrome

PMID:
29614955
PMCID:
PMC5883342
DOI:
10.1186/s12881-018-0563-3
[Indexed for MEDLINE]
Free PMC Article

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