Molecular characterization of severe progressive encephalopathies in childhood

Progressive encephalopathies (PE) in children are clinically and genetically heterogeneous. Affected individuals usually exhibit developmental arrest before regression, and cerebral MRI show loss of neural tissue or abnormal signaling intensity. Our aim is to identify disease-causing genetic variants in undiagnosed PE and to perform functional analyses in novel disease genes.

In this project our collaborator Professor Petter Strømme (Department of Pediatrics, OUS/UiO) has so far included more than 100 patients from 70 families negative for known lysosomal, mitochondrial, peroxisomal, and amino- and organic acid, and other relevant metabolic and degenerative diseases with no history of infectious diseases or perinatal hypoxia.

We have performed Whole Exome Sequencing (WES) in family trios (one child and parents) or inverted trios (two children and one parent) followed by filtering of the WES data (population frequency, estimated severity of variants, inheritance pattern). Hypotheses about the molecular consequences of the genetic variants detected are explored in vitro in patient cells and in vivo using animal models (C. elegans, zebrafish, mice).

We have detected the disease causing gene variant in about 50% of the families analyzed including more than 20 novel mutations in previously described disease genes (Table). In six families the genetic findings immediately led to a change in treatment options: e.g. diet adjustment, hematopoietic stem cell transplantation (HSCT), or experimental medication.

In our work we have published several novel disease entities and characterized disease-causing variants in genes not previously linked to human disease.

In WES-negative families we have continued Whole Genome Sequencing (WGS) and RNA-sequencing (RNAseq) in order to detect disease causing variants outside the exome and to detect structural variants. WES, WGS and RNAseq are performed at the Norwegian High-Throughput Sequencing Centre, NSC.

Examples from this work:

  • Barøy et al. (2015). A Novel Type of Rhizomelic Chondrodysplasia Punctata, RCDP5, Is Caused by Loss of the PEX5 Long Isoform. Hum Mol Genet 24:5845-54.
  • Lemke et al. (2016). Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy. Neurology 86:2171-8.
  • Gabriele et al. (2017). YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction. Am J Hum Genet 100:907-925.
  • Kotlarz et (2018). Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy. Nature Genetics 50(3):344-348.
  • Strømme et al. (2018). Mutated thyroid hormone transporter OATP1C1 associates with severe brain hypometabolism and juvenile neurodegeneration. Thyroid 28:1406-1415.


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