Karyotyping: from microscope to array - II

Scientific case and motivation

In December 2007 a Workshop was held at the Lorentz Center entitled: Karyotype from microscope to array. This Workshop was attended by representatives of all the cytogenetic laboratories and clinical genetic centres in The Netherlands and Flanders. The purpose of this Workshop was to facilitate the switch from the application of microscopic to molecular techniques for the genome wide detection of chromosomal rearrangements.

Several array platforms and the accompanying software for data analysis were demonstrated in hands on sessions. Also, the international databases on genomic variants, both ‘normal’ and pathogenic were introduced.

In the course of this year, 2008, all the centres will either be switching their routine diagnosis to array analysis, or perform conventional karyotyping in parallel with array analysis of selected patients.

Karyotyping patients using arrays carrying either clones or oligonucleotides enables the detection of molecular aberrations at unprecedented resolution. Apart from technical problems that may occur with routine use of arrays in the diagnostic laboratory, and the implementation of various software tools for data analysis, the biggest challenge is the interpretation of the large number of variants that is detected in patient DNA.

Initial results clearly show that there are at least three categories of chromosomal aberrations:

1. Polymorphisms with no apparent clinical significance

2. Deletions and duplications that are found frequently de novo in patients, but that are found to be familial in a minority of cases (del22q11; del16p11.2)

3. Rearrangements which are clearly pathogenic.

Of course it is the increasing number of variants in category 2 that needs particular consideration.

The purpose of this second workshop on molecular karyotyping is to assess progress in this fast moving field in the clinical genetic centres in The Netherlands and Flanders, to compare performance of the various array platforms in use, and to discuss collaboration in the analysis and interpretation of array data.

Congenital malformations and/or mental retardation can have many different causes, both genetic and environmental. It is becoming increasingly clear that the plasticity of our genome is the main cause of these important health problems. The genomic analysis of large numbers of patients at much higher resolution will help to understand the etiology and pathogenesis of these disorders which will improve patient care as well as genetic counselling of families at risk.

A close collaboration between the clinical genetic centres will speed up the implementation of the new techniques, and will facilitate the correct interpretation of the huge number of new genome variants that will be detected.