The aim of the project is to identify genetic and molecular basis of congenital brain malformation caused by dysfunction of primary cilia. Structural or functional defects or insufficient number of cilia can result in isolated or multiple organ abnormalities, called ciliopathies. These are rare or ultra-rare diseases remarkable for the phenotypic and genetic heterogeneity and for the phenotypic overlaps.

In the brain, primary cilia play crucial roles for development, neuronal connectivity and survival. Ciliary dysfunction is associated with a wide range of congenital brain malformations, comprising mid-hindbrain malformation, migration disorders or the absence of major brain structures. More than 200 ciliopathies have been defined clinically and genetically and the number is raising, as new ciliopathies are identified. More than 50% of patients with ciliopathies remained without a genetic diagnosis after diagnostic WES or WGS analyses. Thus, an improved diagnostic offer is needed. In addition, there is a major knowledge gap about how defects in the primary cilium affect signaling transduction pathways resulting in brain malformations. Our project aims to obtain knowledge about the pathophysiological mechanisms in ciliopathies.

We study patients with congenital brain malformations compatible with a ciliopathy who lack a molecular diagnosis after diagnostic analyses (WES or WGS) of established morbid genes, thus increasing the possibility to identify genes not yet known to cause brain malformations. Putative novel disease causing genes are shared through GeneMatcher (genematcher.org) to identify independent patients with a similar phenotype and a potentially pathogenic variant in the same gene. The cilia defects caused by the genetic variants are characterized in patient fibroblasts using IF approaches and RNA-sequencing. With our collaborators, we use zebrafish to reveal the effects of the pathogenic variants on cilia structure and function, and on downstream signal transduction pathways.

This approach will allow us to identify novel ciliopathy genes and disease mechanisms causing congenital brain malformations, study genotype-phenotype correlations and at the same time expand the experimental framework, which is important for the evaluation of variant pathogenicity and relevant for all genetic diseases.

We are currently recruiting patients to this project.

Project leader
Doriana Misceo doriana.misceo@medisin.uio.no
Visiting address/postal address: Ullevål sykehus, Kirkeveien 166, bygg 25 (Laboratoriebygget), 0450 Oslo

Medical research students
Alexandra Gløersen

Patient recruitment and clinical investigations:
Prof. P. Strømme (Department of Pediatrics, OUS) and Prof. B. Paus, Dr. I-L. Mero, Dr. Y. Sejersted, and Dr. O Røsby (AMG)
In vivo experiments: Prof. C.V. Esguerra (NCMM, UiO)
In vitro experiments: Prof. C.A.M. Progida (IBV, UiO) 

1. Sumathipala D, Strømme P, Gilissen C, Einarsen IH, Bjørndalen HJ, Server A, Corominas J, Hassel B, Fannemel M, Misceo D, Frengen E (2020)
   Sudden death in epilepsy and ectopic neurohypophysis in Joubert syndrome 23 diagnosed using SNVs/indels and structural variants pipelines on WGS data: a case report
   BMC Med Genet, 21 (1), 96
   DOI 10.1186/s12881-020-01024-y, PubMed 32381069
2. Epting D, Senaratne LDS, Ott E, Holmgren A, Sumathipala D, Larsen SM, Wallmeier J, Bracht D, Frikstad KM, Crowley S, Sikiric A, Barøy T, Käsmann-Kellner B, Decker E, Decker C, Bachmann N, Patzke S, Phelps IG, Katsanis N, Giles R, Schmidts M, Zucknick M, Lienkamp SS, Omran H, Davis EE et al. (2020)
   Loss of CBY1 results in a ciliopathy characterized by features of Joubert syndrome
   Hum Mutat, 41 (12), 2179-2194
   DOI 10.1002/humu.24127, PubMed 33131181