Sanna Gudmundsson

TRANSLATIONAL OMICS TEAM

Mission: Accelerating implementation of precision medicine for genetic disease

More than 50% of rare disease patients remain undiagnosed, highlighting our limited understanding of rare disease biology and our ability to predict the effects of human genomic variants. Our research aims to improve variant interpretation by leveraging large-scale omics datasets, such as reference population data from gnomAD, GTEx, and dGTEx, and rare disease datasets such as the Genomic Medicine Center Karolinska (CMG) rare disease cohort and the Broad Center for Mendelian Genomics (GREGoR). We are especially interested in mechanisms underlying incomplete penetrance and investigate its prevalence, mechanisms, and methods to predict penetrance by studying individuals with disease variants who remain unaffected or show milder phenotypic expression of disease. Collectively, our ongoing projects aim to improve genetic diagnostics with novel understanding and tools that accelerate the implementation of precision medicine for rare disease patients

Recruting
Graduate students looking to pursue thesis work or other internships working with international large-scale datasets are welcome to reach out with a CV. All PhD, postdoc, and research assistant positions are openly announced and also posted on LinkedIn; welcome to connect and reach out with any questions.

Ongoing projects

Methods to predict incomplete penetrance

This project addresses one of the key unresolved challenges in rare disease genomics: predicting whether a pathogenic variant will result in disease. By combining complete-genome sequencing, methylation profiling and multi-omics data, the project will identify molecular determinants of incomplete penetrance and variable expressivity and develop approaches for penetrance prediction. The work extends the network's focus on complete genomics from variant detection to clinical interpretation, supporting improved diagnosis, risk assessment and implementation of multi-omic methods in genomic medicine.

Advancing per-base expression scores (pext)

The impact of a genetic variant can depend on when and where a gene’s transcripts are expressed. We use large-scale RNA sequencing data from the developmental GTEx project to extend pext, a measure of transcript expression, across developmental stages and tissues. Our goal is to improve the interpretation of rare disease variants by identifying those that affect transcripts important during development but poorly represented in adults. A pilot analysis is included in the dGTEx flagship paper.

Incomplete penetrance in rare disease cohorts

Why do some people carry a disease-causing variant without developing the associated disorder? We study rare disease cohorts and their families to investigate incomplete penetrance and understand why the same variant can have different effects across individuals. By combining genomic data with clinical information and detailed variant evaluation, we aim to improve variant interpretation and rare disease diagnosis (preprint).

Using population genomics to improve variant interpretation

We use large-scale population datasets to improve interpretation of rare disease variants. Our work in gnomAD (Nat. Commun.), and on LoF variant interpretation (AJHG), showed how detailed assessment of predicted loss-of-function variants can distinguish true disease-associated variation from annotation errors and variants with limited functional impact. Building on this work, we are analysing long-read genome sequencing data from 1, 500 SCAPIS participants, combining genetic variation with detailed clinical information to better understand its consequences and disease penetrance.