Clinical Impact of Proximal Autosomal Imbalances

Abstract

Centromere-near gain of copy number can be induced by intra- or inter-chromosomal rearrangements or by the presence of a small supernumerary marker chromosome (sSMC). Interestingly, partial trisomy to hexasomy of euchromatic material may be present in clinically healthy or affected individuals, depending on origin and size of chromosomal material involved. Here we report the known minimal sizes of all centromere-near, i.e., proximal auto-somal regions in humans, which are tolerated; over 100 Mb of coding DNA are comprised in these regions. Additionally, we have summarized the typical symptoms for nine proximal autosomal regions including genes obviously sensitive to copy numbers. Overall, studying the carriers of specific chromosomal imbalances using genomics-based medicine, combined with single cell analysis can provide the genotype-phenotype correlations and can also give hints where copy-number-sensitive genes are located in the human genome.

Diagnostic utility of microarray testing in pregnancy loss

“…Variability in mosaicism levels between fetal samples, detection thresholds and differential cell line growth in culture explain why mosaic results may only be seen on karyotype (Table ) or microarray (Table ). For marker chromosomes, microarrays will give normal results if the marker does not contain euchromatic material; this is useful, since heterochromatic markers are unlikely to cause phenotypic abnormalities. Finally, whereas aCGH alone cannot detect female triploidy, SNP arrays detect all triploidies.…”

Small Supernumerary Marker Chromosome May Provide Information on Dosage-insensitive Pericentric Regions in Human

“…Furthermore, carriers of small supernumerary marker chromosomes (sSMCs) represent the largest subgroup among healthy persons living with chromosomal imbalances [ 7 , 9 ]. The identification of such healthy sSMC carriers with centromere-near imbalances in the range of several Mbps led to the proposal, that these euchromatic regions being present in three or more copies do not contain any dosage sensitive genes [ 9 , 10 ]. Thus, those sSMC-carriers can be regarded as ideal models to characterize the dosage-insensitive stretches in human pericentric regions.…”

Partial tetrasomy of the proximal long arm of chromosome 15 in two patients: the significance of the gene dosage in terms of phenotype

“…reported in the context of pericentric human chromosomal regions, that dosage dependent and dosage independent genes could stand in the background of the clinical effects of the sSMCs. He stated, that sSMCs containing only dosage independent genes could be harmless, while dosage dependent genes in the marker chromosomes could lead to clinical problems [ 36 ].…”