Abstract
BackgroundMolecular 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.MethodsWe 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.ResultsWe 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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-014-0070-0) contains supplementary material, which is available to authorized users.
Highlights
Molecular karyotyping is 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
The main differences resides in the total number of CNV calls that had to be interpreted for each patient (Table 4), which ranged from an average of 1.7 per patient for Omni1 and 0.4 for CytoSNP, to 6.6 for single nucleotide polymorphism (SNP) 6.0, and the proportion of patients for whom we identified at least one variants of uncertain clinical significance (VOUS), which was 14.3% for CytoSNP (3/21), 33.3% for Omni1 (7/21) and 95.2% for SNP 6.0 (20/21)
As a result of the homozygous mutations uncovered, the overall diagnostic yield was higher (28.6%, 6/21) than the yield we would have obtained with the platform we currently use (14.3%, 3/21), as well as the yield reported in previous studies using high resolution SNP arrays but restricted to CNV detection, which ranges from 4.4% to 16% [36,37,38,39,40]
Summary
Molecular karyotyping is 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. 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. An important number of chromosomal aberrations that are thought to be benign, or for which clinical significance currently cannot be determined, are being identified [13], requiring cytogenetics laboratories to store and share genotype-phenotype data in order to provide the most accurate clinical interpretation for each result
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