• Deborah Bartholdi and Peter Miny.
• Institut für Klinische Genetik, Klinikum Stuttgart.
• Ther Umsch. 2013 Nov 1; 70 (11): 621-31.

AbstractNew key technologies such as array-based molecular karyotyping and high throughput sequencing are currently introduced in pre- and postnatal diagnostic testing. These greatly improved genomic testing approaches are beginning to fundamentally change diagnostic strategies in the clinical setting. Molecular karyotyping in the fetus is now routinely performed in high risk situations or on parental request. It will replace the conventional microscopic approach in the near future. Non-invasive prenatal testing to exclude common trisomies is probably the most significant recent achievement and has the potential to dramatically reduce invasive testing. Multiple congenital malformations and intellectual disability (ID) occur in up to 3 % of the general population. A correct diagnosis at an early age is important for clinical management of the patients and for counselling the families with regard to recurrence risk. Conventional karyotyping has been replaced by molecular karyotyping (microarray analysis, Array-CGH), increasing the diagnostic yield up to 15 - 20 % in this population. This approach can be challenging with regard to interpretation of copy number variants of uncertain significance or variants with reduced penetrance. If the clinical assessment leads to the suspicion of a specific syndrome or a leading symptom like epilepsy or microcephaly is present, genetic testing might be directed towards single-gene analysis. However, increasing knowledge indicates that many of these conditions are genetically heterogeneous. The availability of next-generation sequencing techniques has led to the implementation of testing panels in the diagnostic setting, by which multiple genes are analyzed in parallel. This approach allows for increased diagnostic yield in monogenic disorders and defining of more detailed genoptype-phenotype correlations. In addition, whole-exome or whole-genome sequencing has led to the identification of the genetic basis of many known genetic disorders and to the identification and delineation of novel disorders thus allowing a diagnosis in more patients. Fulfilling the potential of the increasing number of options for genetic testing for accurate diagnosis requires close collaboration between clinical geneticists and paediatricians.

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