Bondeson and Annerén's projects – Next-Generation Sequencing for exploratory research and clinical implementation

Clinical and genetic investigation of rare ID syndromes

Marie-Louise Bondeson, Christian Wentzel, Cecilia Soussi Zander, Berivan Baskin, Göran Annerén, Sanna Gudmundsson, Maria Wilbe, Ann-Charlotte Thuresson

Intellectual disability (ID) affects approximately 1–2 % of the population. To date, over 700 genes have been associated with ID but the genetic cause remains unknown in 30–45 % of families. This suggests that there is a comprehensive underlying genetic heterogeneity among patients with ID and that there is still numerous of genes to identify. Approximately 250 patients per year are analysed at Clinical Genetics, Uppsala University Hospital by using chromosomal microarray analysis (CMA), with a detection rate of approximately 15 %. Studies have shown that whole exome sequencing (WES) will detect the genetic cause in additional 25–30 %.

The recommended genetic investigation for ID today is CMA, and if negative followed by WES. In selected groups of patients, where no chromosomal aberration has been detected, they can be recruited to research. Next generation sequencing (NGS) technologies are used to screen the genomes of patients at high resolution to identify new causative genes for ID, which are further evaluated with functional assays that characterizes their molecular function. 

Clinical and molecular characterization of Noonan spectrum disorders (RASopathies)

Sanna Gudmundsson, Maria Wilbe, Berivan Baskin, Cecilia Soussi Zander, Göran Annerén, Marie-Louise Bondeson

Recent advances in molecular genetic research have led to the definition of a new group of genetic syndromes, the RAS/MAPK pathway disorders or ”RASopathies”. They comprise Noonan syndrome and related disorders (Noonan with multiple lentigines, Cardio-facio-cutaneous and Costello syndromes), as well as Neurofibromatosis type 1.

The aim of this study is to enable translational research into disease mechanism and therapies of RASopathies. The RAS/MAPK pathway, which has been well studied in cancer, is an attractive target for inhibition in the treatment of various malignancies utilizing small molecule therapeutics, which specifically inhibit the pathway.

The specific aims of the project are to identify novel causative genes associated with RASopathies using NGS and to investigate the functional role of different mutations in the RAS/MAPK pathway to clarify the underlying molecular mechanisms.

Schematic illustration of signalling pathway
The RAS-MAOK signal transduction pathway and the RASopathies associated
with dysregulation of various components if the pathway (adopted from Ekvall et al.
Am. J. Med Genet. 2011, 155(6):12-17-24).


Clinical and molecular characterization of intrauterine fetal death (IUFD)

Maria Wilbe, Sanna Gudmundsson, Carina Frykholm, Katharina Ericson, Marie-Louise Bondeson

The miscarriage rate among pregnant women is 15–20 %. Aneuploidy and unbalanced chromosomal abnormalities account for 50–60 % of fetal loss during this period, most of which have occurred de novo. Recent studies have shown that almost a third of early fetal losses had genetic abnormalities detected by microarray analysis. However, in the majority of cases with recurrent fetal loss the genetic etiology is still unknown.

This research project aims to identify and characterize the genetic abnormalities that can cause IUFD by examining the genome in affected families. Families recruited to the study have been comprehensively investigated genetically and as a last option, participation in this research project is offered. This enables prenatal diagnosis for the affected family. Moreover, increased knowledge about the genetic etiology of fetal loss in pregnancy will contribute to better understanding of the fetal development and will also enable improved genetic diagnostics.