SNP arrays: comparing diagnostic yields for four platforms in children with developmental delay

BMC Medical Genomics

Emmanuelle Lemyre⁵  Jacques L Michaud⁵  Michael S Phillips²  Frédérique Tihy⁴  Myriam Srour³  Sonia Nizard⁵  Raouf Fetni⁴  Géraldine Mathonnet¹  Mathieu Langlois²  Guylaine D’Amours⁶ 

[1] Service de génétique médicale, CHU Sainte-Justine, Montréal, QC, Canada;Centre de pharmacogénomique, Institut de cardiologie de Montréal, Montréal, QC, Canada;Centre de recherche, CHU Sainte-Justine, Montréal, QC, Canada;Pathologie et biologie cellulaire, Université de Montréal, Montréal, QC, Canada;Pédiatrie, Université de Montréal, Montréal, QC, Canada;Faculté de médecine, Université de Montréal, Montréal, QC, Canada

关键词: Uniparental disomy (UPD);    Single nucleotide polymorphism (SNP);    Microarray analysis;    Loss of heterozygosity (LOH);    Intellectual disability;    DNA copy number variation (CNV);    Consanguinity;    Congenital abnormalities;    Comparative genomic hybridization (CGH);   

Others  :  1090065
DOI  :  10.1186/s12920-014-0070-0

 received in 2014-05-06, accepted in 2014-12-11,  发布年份 2014

【 摘 要 】

Background

Molecular karyotyping is now the first-tier genetic test for patients affected with unexplained intellectual disability (ID) and/or multiple congenital anomalies (MCA), since it identifies a pathogenic copy number variation (CNV) in 10-14% of them. High-resolution microarrays combining molecular karyotyping and single nucleotide polymorphism (SNP) genotyping were recently introduced to the market. In addition to identifying CNVs, these platforms detect loss of heterozygosity (LOH), which can indicate the presence of a homozygous mutation or uniparental disomy. Since these abnormalities can be associated with ID and/or MCA, their detection is of particular interest for patients whose phenotype remains unexplained. However, the diagnostic yield obtained with these platforms is not confirmed, and the real clinical value of LOH detection has not been established.

Methods

We selected 21 children affected with ID, with or without congenital malformations, for whom standard genetic analyses failed to provide a diagnosis. We performed high-resolution SNP array analysis with four platforms (Affymetrix Genome-Wide Human SNP Array 6.0, Affymetrix Cytogenetics Whole-Genome 2.7 M array, Illumina HumanOmni1-Quad BeadChip, and Illumina HumanCytoSNP-12 DNA Analysis BeadChip) on whole-blood samples obtained from children and their parents to detect pathogenic CNVs and LOHs, and compared the results with those obtained on a moderate resolution array-based comparative genomic hybridization platform (NimbleGen CGX-12 Cytogenetics Array), already used in the clinical setting.

Results

We identified a total of four pathogenic CNVs in three patients, and all arrays successfully detected them. With the SNP arrays, we also identified a LOH containing a gene associated with a recessive disorder consistent with the patient’s phenotype (i.e., an informative LOH) in four children (including two siblings). A homozygous mutation within the informative LOH was found in three of these patients. Therefore, we were able to increase the diagnostic yield from 14.3% to 28.6% as a result of the information provided by LOHs.

Conclusions

This study shows the clinical usefulness of SNP arrays in children with ID, since they successfully detect pathogenic CNVs, identify informative LOHs that can lead to the diagnosis of a recessive disorder. It also highlights some challenges associated with the use of SNP arrays in a clinical laboratory.

【 授权许可】

   
2014 D'Amours et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

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