Characterization of a cryptic 3.3 Mb deletion in a patient with a “balanced t(15;22) translocation” using high density oligo array CGH and gene expression arrays

Abstract

Patients with an apparently balanced translocation and an abnormal phenotype may carry a cryptic deletion/duplication at their translocation breakpoints that may explain their abnormalities. Using microarray CGH (aCGH) and gene expression arrays we studied a child with t(15;22)(q26.1;q11.2), developmental delay and mild dysmorphic features. A high density aCGH study with 244,000 oligo probes demonstrated a 3.3 Mb deletion immediately adjacent to the 15q breakpoint. Gene expression studies with 44,000 oligos displayed an approximately 50% reduction of the expression of IGF1R gene that was translocated to the der(22). There are 18 known or hypothetical protein coding genes within the deleted region according to UniProt, RefSeq, and GenBank mRNA (UCSC HG17, May 2004). Although two of these genes, RGMA and ST8SIA2, play an important role in neural development, the mild phenotype of our patient indicates that loss of one copy of these genes may not be critical developmentally. The 50% reduction of IGF1R expression could be responsible for the growth deficiency in the patient. Reviewing the few 15q26 microdeletion cases that have been characterized by aCGH, we discovered that deletion of the segment including distal 15q26.2 to the proximal part of 15q26.3 is associated with severe phenotypes. Our experience demonstrates that high-density oligonucleotide-based aCGH is a quick and precise way to identify cryptic copy number changes in "balanced translocations." Expression studies can also add valuable information regarding gene expression changes due to a chromosomal rearrangement. Both approaches can assist in the elucidation of the etiology of unexplained phenotypic differences in cases such as this one.

Detection of cryptic pathogenic copy number variations and constitutional loss of heterozygosity using high resolution SNP microarray analysis in 117 patients referred for cytogenetic analysis and impact on clinical practice

“…The other 10 pathogenic CNVs found (table 1, cases 1–10) are examples of new microdeletion/duplication syndromes that have recently been described, as follows: two cases of thrombocytopenia absent radius (TAR, 30 cases described),15 1q41q42 microdeletion (at least seven cases described to date),16 1q43q44 microdeletion (21 cases of 1qter microdeletion syndrome reported),17 15q13.3 microdeletion (nine patients described to date),18 15q26 microdeletion (six patients described to date by Li et al ),19 16p11.2 microdeletion (at least 25 cases described to date),20 – 23 17q21.31 microdeletion (at least 22 cases described to date),24 20q13.33 deletion (one case described by Béna et al ),25 and 22q11.2 microduplication (two cases described to date)26 syndromes. These CNVs contained between 7 and 869 SNPs and ranged in estimated size from 214 Kb to 8.9 Mb, median 1.95 Mb.…”

CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures

“…Intellectual disability was mild to severe. 11,[14][15][16][17] The missense, nonsense, frameshift, and splice site mutations in CHD2 encephalopathy do not cluster in any definite pattern within the gene (figure 4), and the location or type of mutation does not correlate with disease severity. CHD2 is among the genes that are most intolerant to functional variation (ranked in top 2.5%).…”

Detection of genomic imbalances in microdissected Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma by array-based comparative genomic hybridization

“…Gains and losses were defined by use of the Aberration Detection Method-2 (ADM-2) algorithm of the CGH Analytics software with a threshold of 6.0. 25 Significant chromosomal gains detected by the ADM-2 algorithm with an average log2-ratio exceeding 0.8 were classified as amplifications. Copy number variations/polymorphisms were identified with a database integrated in the Agilent CGH Analytics software and excluded from further analyses.…”