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

Conny M.A. van Ravenswaaij-Arts (1) , Birgit Sikkema-Raddatz (1) , Gerben van Der Vries (1) , Trijnie Dijkhuizen (1) , Nicolien M. Hanemaaijer (1) , Roel Hordijk (1) , Ton J. van Essen (1) , Irma (h.) E. Veenstra-Knol (1) , W S Kerstjens-Frederikse (1) , J C Herkert (1) , Erica Gerkes (1) , Beike (l.) K. Leegte (1) , Klaas Kok (1) , Richard J. Sinke (1)

1 Department of Genetics

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 4 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 7,912 kb in size and were significantly larger than benign gains and gains of unknown clinical relevance (p<0.001). Our study showed that a threshold of 200 kb is acceptable in a clinical setting, while 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.

Mots clés: genome-wide array analysis; copy number gains; guideline

Domaines: Génétique

Conny M.A. van Ravenswaaij-Arts, Birgit Sikkema-Raddatz, Gerben van Der Vries, Trijnie Dijkhuizen, Nicolien M. Hanemaaijer, et al.. Practical guidelines for interpreting copy number gains detected by high-resolution array CGH in routine diagnostics. European Journal of Human Genetics, 2011, ⟨10.1038/ejhg.2011.174⟩. ⟨hal-00681221⟩