Single Nucleotide Polymorphism (SNP) Array

Definition and Principle

Single Nucleotide Polymorphism (SNP) arrays represent an advanced form of chromosomal microarray. Instead of comparing patient DNA to a reference sample, SNP arrays hybridize patient DNA to probes specific for hundreds of thousands of known SNPs (single base-pair variations) distributed across the genome. It detects not only Copy Number Variants (via signal intensity) but also the genotype (allele variations) at each locus.

Unique Capabilities of SNP Arrays

While SNP arrays perform the standard function of detecting microdeletions and microduplications (like aCGH), their distinct clinical value lies in analyzing allelic zygosity.

1. Detection of Absence of Heterozygosity (AOH)

• AOH (also termed Loss of Heterozygosity or LOH) refers to continuous stretches of homozygous SNPs without a corresponding change in copy number.
• Normal individuals have a mix of heterozygous and homozygous SNPs. Extensive AOH flags regions where both chromosomal copies are identical.

2. Identification of Uniparental Disomy (UPD)

• Occurs when an individual inherits both copies of a chromosome (or part of a chromosome) from one parent and no copy from the other.
• SNP arrays can detect isodisomy (inheritance of two identical copies of one parental homolog), presenting as AOH on a specific chromosome.
• Clinical Relevance: Crucial for diagnosing imprinting disorders such as Prader-Willi Syndrome (maternal UPD 15) and Angelman Syndrome (paternal UPD 15) when deletion analysis is negative.

3. Detection of Consanguinity and Identity by Descent

• Multiple blocks of AOH distributed across different chromosomes indicate that the parents share a common ancestor.
• Clinical Relevance: Allows for the estimation of the degree of parental consanguinity. It helps narrow down candidate regions for homozygosity mapping when searching for an underlying autosomal recessive disorder.

4. Detection of Triploidy and Molar Pregnancies

• Traditional aCGH can miss whole-genome triploidy if the test compares patient DNA against sex-matched control DNA (since the ratio remains balanced).
• SNP arrays identify triploidy by demonstrating three distinct alleles (e.g., AAA, AAB, ABB, BBB) across all loci, making it highly valuable in evaluating products of conception.

Limitations Specific to SNP Arrays

• Like aCGH, SNP arrays cannot detect balanced translocations or point mutations.
• Detection of UPD is limited to isodisomy (identical alleles). Heterodisomy (inheritance of two different homologs from the same parent) will retain heterozygosity and may be missed without direct comparison to parental SNP arrays (trio analysis).