NOVEL - De NOvo genetic Variants in Embryonic development and early Lethality

General Background
Next generation sequencing is the new workhorse of genetics for studying congenital malformations, mental retardation, and inherited diseases. Indeed, by using this approach I and others have recently been able to identify several genes underlying these disorders. So far, however, attention has mainly been focused on viable disorders and the 1% of the DNA that encodes proteins, known as the exome.

An important reason why Mendelian disease genes are not always easily detected, can be early lethality. Pathologic pregnancies are one of the major health burdens of our society, as just 25% of all conceptions lead to a liveborn child. One quarter of all conceptions are already lost prior to implantation, additional 33% during the blastomere state. Approximately 15% of all pregnancies end as a spontaneous abortion (6-28wks of gestation), 1-2% end as stillbirths. It is known that chromosomal aneuploidies can explain up to 60% of spontaneous abortion and 6% of stillbirth. The rate of chromosome aberrations is particularly high in cases of pregnancy loss associated with congenital malformations, (>50%), fetuses with normal differentiation show a much lower prevalence of chromosome aberrations (1-2%). Recent studies of copy number variants (CNVs) have confirmed this. Although point-mutations are known to cause pregnancy loss, a systematic genomewide study has not been performed yet, leaving a large proportion of pregnancy losses unexplained.

Identification of: (1) mutations that cause embryonic lethality, resulting in pregnancy loss, and (2) mutations that are located outside the protein coding regions of the genome.

In this study I will study selected cases of pregnancy loss exhibiting well-defined malformations for coding and non-coding mutations leveraging latest next generation sequencing technologies. 1.) Exome sequencing will allow identification of genes with functions crucial for early development in humans. Such mutations would never be observed in liveborns. 2.) Cases of pregnancy loss with congenital malformations that do not exhibit causative variants in the coding part of the genome (the exome) will be subjected to whole genome sequencing with specific emphasis on the ‘regulatome’, which represents ~3% of the non-protein coding part of the human genome and consists of evolutionarily highly conserved non-coding elements (CNCs) or other know regulatory elements (e.g. ENCODE).

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