Líffræðifélag Íslands - biologia.is
Líffræðiráðstefnan 2017

Erindi/veggspjald / Talk/poster E76

Large-scale genetic research may hold the key to solving rare disease cases

Höfundar / Authors: Gudny A. Arnadottir (1), Brynjar O. Jensson (1), Sigurdur E. Marelsson (2), Asmundur Oddsson (1), Ragnar P. Kristjansson (1), Stefania Benonisdottir (1), Gudmundur A. Thorisson (1), Daniel F. Gudbjartsson (1,3), Unnur Thorsteinsdottir (1,4), Reynir Arngrimsson (4,5), Patrick Sulem (1), Kari Stefansson (1,4)

Starfsvettvangur / Affiliations: 1. deCODE Genetics/Amgen, Inc., 2. Department of Pediatrics, Landspitali University Hospital, 3. School of Engineering and Natural Sciences, University of Iceland, 4. Faculty of Medicine, University of Iceland, 5. Department of Genetics and Molecular Medicine, Landspitali University Hospital

Kynnir / Presenter: Guðný Anna Árnadóttir

Studying molecular causes of rare diseases benefits from large-scale genetic research, as exemplified by our recent success in solving several undiagnosed cases of rare disease in Iceland.
Through whole-genome sequencing we detected a compound heterozygous genotype in UBA5 in two sisters with epileptic encephalopathy. UBA5 encodes an activating enzyme for ufmylation, a post-translational modification pathway, and is the first gene from that pathway to be linked to disease (in 2016). Using our reference set of 30,067 whole-genome sequenced Icelanders, we were able to conclude that the UBA5 genotype was private to the affected sisters. One of the compound heterozygous mutations resulted in loss-of-function of one allele of UBA5. The other, p.Ala371Thr, had been reported previously as pathogenic only when combined with another loss-of-function mutation in UBA5. Using our set of 150,656 chip-genotyped Icelanders, we identified three Icelanders homozygous for p.Ala371Thr. These individuals showed no signs of neurological disease, which confirms that p.Ala371Thr acts as a hypomorphic mutation.
We will also present three other examples that show how genetic research can give an insight into molecular mechanisms of rare disease cases: An X-linked mosaic de novo mutation causing Congenital disorder of metabolism, parental germline mosaicism of a de novo mutation resulting in epilepsy in two siblings and RNA sequence data holding the key to solution in a case of Prolidase deficiency.