Practical guidelines for interpreting copy number gains detected by high-resolution array in routine diagnostics

Abstract

The correct interpretation of copy number gains in patients with developmental delay and multiple congenital anomalies is hampered by the large number of copy number variations (CNVs) encountered in healthy individuals. The variable phenotype associated with copy number gains makes interpretation even more difficult. Literature shows that inheritence, size and presence in healthy individuals are commonly used to decide whether a certain copy number gain is pathogenic, but no general consensus has been established. We aimed to develop guidelines for interpreting gains detected by array analysis using array CGH data of 300 patients analysed with the 105K Agilent oligo array in a diagnostic setting. We evaluated the guidelines in a second, independent, cohort of 300 patients. In the first 300 patients 797 gains of four or more adjacent oligonucleotides were observed. Of these, 45.4% were de novo and 54.6% were familial. In total, 94.8% of all de novo gains and 87.1% of all familial gains were concluded to be benign CNVs. Clinically relevant gains ranged from 288 to 7912 kb in size, and were significantly larger than benign gains and gains of unknown clinical relevance (Po0.001). Our study showed that a threshold of 200 kb is acceptable in a clinical setting, whereas heritability does not exclude a pathogenic nature of a gain. Evaluation of the guidelines in the second cohort of 300 patients revealed that the interpretation guidelines were clear, easy to follow and efficient.

Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways

“…Until recently, the interpretation of this type of CNV was considered a challenge in the literature. However, current studies and guidelines indicate its clinical relevance (40). In bioinformatics analysis of the duplication found in patient 6, we identified 14 genes with functions in cell cycle, developmental process, and/or cell growth pathways.…”

Interstitial Chromosome 3p14.1 Deletion due to a Maternal Insertion: Phenotype and Association with Balanced Parental Rearrangement

“…Given this significant risk for all future pregnancies, prenatal diagnosis should be offered to carrier couples for all future pregnancies. Array CGH performed with chorionic villus sampling or amniocentesis should be able to identify sub microscopic unbalanced deletions or duplications in an affected fetus [Hanemaaijer et al, 2012]. In addition, karyotype and specific FISH analysis should be offered for other family members, particularly maternal siblings of child-bearing age in our case.…”

Uniparental Disomy of Chromosome 15 in Two Cases by Chromosome Microarray: A Lesson Worth Thinking

“…The application of CMA in detecting CNVs is well documented and now recommended as a first-tier clini- cal diagnostic test for patients with developmental delay/ intellectual disability, autism, congenital anomalies, and other dysmorphic features, replacing karyotype analysis and some disease-specific tests [Miller et al, 2010;Kearney et al, 2011;Hanemaaijer et al, 2012;South et al, 2013]. With the broadest genomic coverage, the Affymetrix CytoScan HD array provides the highest performance for detecting human chromosomal aberrations.…”