Marie-Louise Bondeson – Massive Parallell Sequencing for exploratory research and clinical implementation

Clinical and genetic investigation of rare intellectual disability syndromes

Intellectual disability (ID) affects approximately 1–2% of the population. To date, over 1500 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 and molecular mechanisms to identify.

At Clinical Genetics, Uppsala University Hospital, approximately 1500 patients with ID are investigated per year. Despite extensive genetic analysis, including whole exome or whole genome sequencing, a large number of patients will not receive a genetic diagnosis.

Today, primarily short-read sequencing is used for the detection of genetic variants. However, this technique struggles to read through the so-called “dark regions” of the genome, which often contain repeated sequences where pathogenic copy number variations, structural variants and expansions occur at a high frequency. In this project our aim is to use state-of-the-art sequencing technologies, including transcriptome- and long-read sequencing technologies, to identify the underlying genetic cause in unsolved cases.

Clinical and molecular characterization of intrauterine fetal death (IUFD)

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.