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FORM: Fetal Phenomics to unravel the correlation between phenotype and genotype in prenatal malformations

Research Project | 3 Project Members

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.

Ethical considerations in pediatric genome-wide sequencing

Research Project | 5 Project Members

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.

Massively parallel Sequencing for gene discovery in lethal fetal disorders

Research Project | 2 Project Members

The announcement of a serious or even lethal condition during pregnancy or at birth is a devastating experience for the parents and the health professionals involved. The demand for the determination of the cause is high, not only for psychological reasons, but also for determining pregnancy and perinatal management, recurrence risks as well as counseling for subsequent pregnancies. Malformations and genetic disorders are the leading cause of infant mortality in the developed countries accounting for more than one third of cases; more than 70% present with organ malformations. Today, major, also potentially lethal, malformations are often already detected prenatally during ultrasound examination. The prevalence of malformations during fetal development is even higher, because a proportion of these pregnancies will not survive until birth. In about 10-15% the genetic origin is due to chromosome anomalies including submicroscopic anomalies detected by chromosomal microarrays. In the remaining patients genetic testing for mutations in single genes can only be offered if a clinical diagnosis of a specific disorder is suspected. Novel high-throughput next generation sequencing technologies have now enabled the discovery of many novel genes in children with developmental impairments. However, only little attention has been paid to using these sequencing strategies for gene identification in human malformation syndromes that are lethal in utero or at birth despite their frequency and their importance in pregnancy and newborn health care. Aim: In this project we will use massively parallel genomic sequencing for gene identification in deceased fetuses and newborns with multiple malformations of unknown cause after normal chromosomal array analysis. The general goal of this project is to identify disease genes where mutations lead to autosomal recessive forms of these lethal conditions. Hypotheses: We test the hypotheses that (1) massively parallel sequencing of all protein-coding regions in the genome (exome sequencing) can identify novel genes by detecting the mutations that cause malformations in fetuses and newborns in whom such etiological factors exist, that (2) autosomal recessive mutations are an important cause of early human lethality and 3) the comparison of human and animal morphology - cross-species phenotyping - is an important means to validate novel potentially causal genes. Methods: We select families in which at least two children (and at least one girl) died during pregnancy or after birth because of their malformations. The malformation pattern can be correlated to a particular developmental pathway in embryogenesis. Genes with homozygous or compound heterozygous mutations will be considered candidate genes. In order to investigate the causality of mutations, the expected inheritance of these recessive candidate mutations will be confirmed in the family, and the absence of these variants in normal populations will be confirmed by analysis of the publicly available genome sequences of unaffected individuals. A critical aspect of this project is genotype-phenotype correlations of candidate genes in which we will include developmental pathway analysis and cross-species phenotyping using animal models. Relevance: Malformations and genetic disorders are the leading cause of prenatal and newborn mortality in the developed countries. Knowledge of the impact of genetic diseases on mortality is important for the integration of preventive measures and health care strategies to care appropriately for patients and their families. Our approach will provide a means of obtaining the genetic cause for fatal malformation syndromes for whom this is not currently available. We expect to discover previously unknown autosomal recessive genes, to discover novel mutations in known genes which have not been yet associated with fetal or perinatal human death and to describe novel prenatally observed syndromes which have not been recognized before. The comparison of human and animal morphology allows validating genes involved in those unrecognized and so far neglected conditions. Complementary to the current large scale international efforts to characterize lethal malformations and causal genes in mice we will focus on increasing our knowledge about normal and abnormal human development. The genes identified may also serve as candidate genes for the cause of similar non-lethal conditions through different mutational mechanisms which would not have been recognized otherwise. Ultimately, families and health care professionals will benefit from novel care and treatment approaches based on the research into these biological mechanisms.