Pathogenic aberrations revealed exclusively by single nucleotide polymorphism (SNP) genotyping data in 5000 samples tested by molecular karyotyping

Abstract

These results demonstrate the utility of SNP genotyping data for detection of clinically significant abnormalities, including chimerism/mosaicism and recessive Mendelian disorders associated with autozygosity. The incidence of clinically significant low level mosaicism inferred from these cases suggests that this has hitherto been underestimated and chromosome mosaicism frequently occurs in the absence of indicative clinical features. The growing appreciation among clinicians and demand for SNP genotyping data poses significant challenges for the interpretation of LCSH, especially where there is no detailed phenotypic description to direct laboratory analysis. Finally, reporting of unexpected or hidden consanguinity revealed by SNP array analysis raises potential ethical and legal issues.

Density matters: comparison of array platforms for detection of copy-number variation and copy-neutral abnormalities

“…Overestimation of total AOH due to false positives or errors in AOH size can erroneously suggest that a given sample exhibits more AOH than that in the general population. Consanguinity is not an uncommon incidental finding in SNP testing, 11,[20][21][22] and AOH findings are not typically confirmed by a second method, so there is a legitimate risk for reporting false-positive AOH results when using LD arrays. AOH results must therefore be reported with these caveats and should never be considered diagnostic for a recessive condition.…”

“…There was a mean of 20 AOH calls (median of 18) per sample detected on the LD array, of which only three regions (~3.5 Mb each) were confirmed by the HD array but not the MD array. These three AOH regions differed in length by [5][6][7][8][9][10][11] Mb between LD and HD platforms. There were also seven small AOH regions (3)(4)(5) in the 11 samples that were detected by the HD array but not by the other arrays (Supplementary Table S2 online).…”

“…By contrast, microarrays can analyze cultured and uncultured samples, thereby uncovering some mosaic abnormalities that escape detection by standard G-band analysis. [9][10][11] Moreover, the combination of allele genotypes (SNP probes) with copy-number data (oligonucleotide probes) in CN+SNP arrays can improve sensitivity and confidence in the detection of mosaicism.…”

Comparison of chromosome analysis and chromosomal microarray analysis: what is the value of chromosome analysis in today’s genomic array era?

“…The low level of mosaicism in these cases cannot be reliably detected by a single-nucleotide polymorphism array either. 12 Case 5 showed mosaicism for a derivative chromosome 8, resulting from an unbalanced translocation between the long arms of one chromosome 8 and one chromosome 21 in 30% of the cultured blood cells. The derivative chromosome 8 resulted in partial trisomy for the distal portion of chromosome 21, which was not detected by CMA.…”

Types of array findings detectable in cytogenetic diagnosis: a proposal for a generic classification

“…Finally, as SNP arrays are nowadays more often employed in diagnostic settings, not only CNVs but also abnormal B-allelic frequencies can indicate a pathogenic finding. 22 Therefore, we suggest broadening the classification to array findings and not narrowing it to CNVs only. Moreover, the proposed classification is generic and potentially may also be applicable for massive parallel sequencing (MPS) findings.…”