REISCHER Theresa

Prenatal Genetic Diagnosis of Congenital Malformations and Genetic Disorders

Since 1966, when the first fetal karyotyp was obtained from cultured amniotic fluid cells, methodology and potential of prenatal genetic diagnosis changed significantly. While resolution of conventional karyotyping improved, also new methods such as chromosomal microarray analysis (CMA) for identifying smaller chromosomal aberrations have been implemented in clinical use.
CMAs can detect chromosomal aberrations 100 times smaller than those found by conventional karyotyping, providing a genome wide analysis of copy number variations (CNV). With the use of CMA an additional detection rate in about 6% of cases with fetal anomalies and in 1.7% of pregnancies with standard indication for prenatal diagnosis (such as advanced maternal age and positive first trimester screening) can be achieved.
Also diagnostics concerning genetic disorders caused by single gene mutations improved due to the growing knowledge about genes and their related disorders and of course due to the progress of technology.
However the majority of fetus with congenital malformations and genetic disorders still remain undiagnosed, especially when common chromosomal imbalances were excluded.

The recent availability of next generation sequencing (NGS) initiated a new era of medical genetics. NGS provides the analysis of wide gene panels up to whole-exome and whole-genome sequencing (WES, WGS), much faster and more cost effective compared to traditional sequencing techniques.
The diagnostic yield of WES in patients with suspected genetic disorders has been reported to be approximately 25%. While investigations so far have focused on gene discovery in postnatal phenotypes, Mendelian conditions or intellectual disability, less attention has been given to gene discovery in fetal disorders.
The aim of our investigations is to improve prenatal genetic diagnosis by use of latest technology partially not implemented in clinical routine by now. We investigate preferentially cases with complex disease entities and poor postnatal outcome to focus on the exploration of development genes. In case of consanguinity, when autosomal recessive diseases are suspected analyses of homozygous segments by means of microarray analysis is conducted to identify candidate genes.
For exome sequencing we define and characterize our study population first by retrospective analysis of fetuses with malformations leading to termination of pregnancies without genetic diagnosis. This is followed by running evaluation of cases in the genetic counseling ambulance and subsequent exome sequencing of single cases.
Finally results of the whole study population will be analyzed to answer the following questions:

-Whats the diagnostic yield of exome sequencing in non-aneuploid fetus with structural malformations?
-Which kinds of genes are mutated in fetuses with such severe clinical outcome?
-Are these identified gene mutations also described in living individuals?
-Is the clinical outcome dependent on the type of mutations of a certain gene (missense vs. nonsense mutations)?
-Is there a genotype phenotype correlation?

Methods and Skills:

Exome sequencing; clinical studies