Prof. Dr. med. Isabel Filges

Background: Birth defects affect 2-4% of all infants and are responsible for 21% of perinatal deaths. The demand to clarify diagnosis, etiology, prognosis, and recurrence risk is high, particularly in the presence of more than one fetal anomaly likely indicating a multiple congenital anomaly (malformation) syndrome. With the advance of prenatal high-resolution ultrasound, fetal anomalies are now detected increasingly early during pregnancy. Prenatal routine high-resolution chromosomal microarray analysis (CMA) and novel exome sequencing technologies allow a genetic diagnosis of causal copy number variants or pathogenic single nucleotide variants in up to additional 40-50 % of pregnancies after the exclusion of the frequent aneuploidies. About 40-60% of families, however, then still remain without definite diagnosis.

Routine exome sequencing (ES) reporting known pathogenic variants in established disease-causing genes in a pregnancy with fetal anomalies has now proven clinical utility. Whole genome sequencing (WGS) is at the verge of being implemented into clinical medicine. For most variants we identify, however, their functional, and therefore also clinical, significance is unknown and for most genes, including those critical for human development, their relation to human disease is not identified. Prenatal phenotypes may differ greatly from postnatal descriptions of the same genetic condition so that integrating prenatal phenotype information into a clinically meaningful interpretation of genomic variants identified is challenging. There is a significant gap between the wealth of data, we can technically generate, and their translation into clinical relevance and utility.

Objectives: The general goal of this project is to describe new genotype-phenotype correlations, through the integration of phenotypic and -omics data to prove causality of novel genomic variants. This will increase our knowledge on the pathogenesis of early human maldevelopment and ultimately improve the clinical utility of prenatal genome-wide sequencing as a one test for all technology in the near future. We explore if 1) using WGS in fetuses with multiple anomalies and no diagnosis after CMA and ES will add additional diagnoses through the identification of additional disease-causing variants, 2) the combined use of WGS with whole transcriptome sequencing on fetal tissues will allow to identify and prove causality of additional variants yet of unknown clinical significance and identify novel phenotype-genotype correlations as well as candidate variants and genes and 3) the the omics approach is potentially amenable for translation into clinical practice. 

Methods: We select families in which at least one pregnancy had a fetus with fetal anomalies for which detailed phenotypic prenatal ultrasound and post mortem examination data from autopsy are available, and no diagnosis was achieved by routine CMA and ES testing. We focus on malformation patterns reminiscent of ciliopathy phenotypes, fetuses with two or more anomalies as well as fetuses with kidney and skeletal anomalies, as for those phenotypes the probability of an underlying monogenic disorder is particularly high. We will perform Trio-WGS of the affected fetus and parents, and transcriptome sequencing on fetal tissues and a control cohort of normal fetuses. We integrate the hierarchical models of phenotype and genotype ontologies for further gene identification.

Relevance: The clinical utility of the future routine application of prenatal genome wide sequencing will largely depend on our ability to increase our knowledge on the specific phenotype–genotype correlations during fetal (anomalous) development and to understand altered developmental pathways specific to fetal life. Novel approaches are needed integrating phenotypes, whole genome and transcriptome data to identify variant effects, novel candidate genes and developmental pathways. Such phenomics approaches ultimately will increase the diagnostic and prognostic value which should be a research priority for sequencing-based prenatal precision medicine.  

Whole exome sequencing (WES) and whole genome sequencing (WGS) are increasingly used in healthcare and research to identify genetic variations, assisting disease diagnosis and prognosis as well as treatment decisions. Besides many potential benefits of WES/WGS for medical care, it also involves a number of important regulatory and ethical challenges. However, there is currently a lack of empirical research on the ethical issues surrounding WGS/WES in Switzerland. It is crucial to investigate the country-specific attitudes, values, beliefs and resulting needs of the relevant stakeholders in Switzerland as an assessment of these is highly valuable for any policy guidance and ethical use of the techniques. The study has the following main objectives:

A . Conduct empirical studies to inform and contextualise the ethical analysis;

• Undertake a systematic qualitative literature review to gather evidence regarding the full spectrum of ethical issues involved in whole-genome/ whole exome-sequencing
• Explore empirically the attitudes of clinical geneticists regarding WGS/WES in Switzerland and Germany
• Explore empirically the attitudes of parents involved in WES of their children in Switzerland

B . Develop normative conclusions with regard to the regulation and practice regarding WGS/WES in Switzerland

The first objective (A) is met by systematic qualitative review methodology and qualitative research methodology (thematic analysis). Semi-structured interviews in Switzerland and Germany are carried out with geneticists and parents of children involved in WES. These exploratory interviews are not based on a predefined understanding on how it should be dealt with WES/WGS, but seek to capture the needs from the perspective of clinical geneticists and parents involved. For the second objective (B) Empirical Bioethics methodologies will be employed. The normative analysis in this project will constantly accompany the empirical data collection. It will concentrate on the overall ethical research question of this PhD: How should be dealt with WGS/WES in an ethical manner in Switzerland - especially regarding children? This thesis adds both to the growing international body of research on responsible and ethically justifiable uses and implementation of new technologies in genomics as well as to filling the gap of research on ethical issues regarding WGS/WES in Switzerland, thus providing key information for Swiss stakeholders in genetics and healthcare services.