Towards the genetic basis of hereditary anosmia in the Faroe Islands
Helena Gásdal Karstensen
Wilhelm Johannsen Centre for Functional Genome Research, Københavns Universitet
Stuðul úr Granskingargrunninum:
In 1969 Lygonis published a large Faroese family without the ability to smell. Of the 52 family members, 19 males and 8 females were affected. Anosmic individuals were observed in all four generations, pointing towards an autosomal dominant inherited trait. Besides the anosmia the pedigree displayed no other abnormalities. Familial anosmia has only been described few times in the literature. So far no causative genes have been identified, probably due to the small size of the pedigrees analyzed. Linkage analysis in two Iranian families, with 9 affected members suggested a 46 cM linkage interval on chromosome 18.
In some syndromic cases, such as Kallmann syndrome where anosmia presents together with hypogonadotropic hypogonadism mutations have been described. They all reside in genes that encode developmental or morphology determining factors in the brain.
The Faroese family, which at present time includes approximately 60-80 individuals in 5-6 generations, comprises a unique study material for genes involved in embryonic development of the brain. The large size of the family and the high number of affected individuals makes it very likely that a causative mutation for the trait will be identified. Ultimately, the project will result in the finding of a novel gene, which will contribute with new knowledge to the understanding of human development, in particular the development of the olfactory system.
At present time, genealogic data of the family, first described by Lygonis is being collected and contact to several family members is already established. The proposed Ph.d project will at the outset take place in the Faroe Islands at the Genetic Resource Centre (Ílegusavnið) and the National Hospital in Tórshavn. Here genealogic data will be collected and clinical, as well as the initial genetic evaluations will be preformed. Subsequent genetic studies will be carried out at the Wilhelm Johannsen Centre for Functional Genome Research at University of Copenhagen, where a comprehensive genetic analysis of the family will take place. The Wilhelm Johannsen Centre has top of the art facilities and experience in research involving mapping and functional characterization of genes involved in normal and abnormal phenotypes. The methods used will include genome wide analysis, high-throughput sequencing and functional studies.
The project will increase the scientific knowledge of the developing brain and the understanding of the human olfactory system. Furthermore, international focus will be attracted to the Faroe Islands as a truly unique source for population studies.
In total 21 individuals with isolated congenital anosmia (ICA) or hyposmia (ICH) along with healthy Faroese control subjects. Affected individuals were identified in four branches of the original family and four cases were apparently sporadic; however, using the Faroese genealogy database the four cases could be traced back to a common ancestor in the 19th century. Initial genetic testing included exclusion of structural variations by karyotyping and disease segregating copy number variants assessed by genome-wide array genotyping (Affymetrix SNP 6.0). No homozygous regions shared among affected individuals were identified. To narrow down a linkage region two branches of the family were selected for linkage analysis assuming dominant inheritance resulting in positive regions on chromosome 5, 10, 12, 13 and 21, totalling 63 Mb, in one branch and regions corresponding to 90,6 Mb on chromosome 2, 4, 5, 7, 9, 14, 16 and 20 in the other branch. However, no regions were overlapping between the two branches of the family, suggesting that more than one locus could be involved in the pathogenesis. To search for mutations within the protein coding part of the genome we carried out whole-exome sequencing in 11 selected individuals. Mutations in the known Kallmann syndrome genes were excluded, in support of a novel genetic mechanism involved in the disorder; however, no non-synonymous disease segregating variants were identified. Considering the rareness of ICA in general, and the massive presence of ICA/ICH in the family, we deem it unlikely that this is not a genetically determined condition(s). However, the linkage data combined with the phenotypic data may support a more complex mode of transmission, involving different loci in different branches.
Of the 21 affected individuals, 18 were examined using magnetic resonance imaging (MRI) to assess structural brain changes in olfactory bulb volume, olfactory sulcus size and cortical gray matter volume. Morphometric measurements showed that ICA and ICH was associated with diminished olfactory bulb volume and olfactory sulcus size. Furthermore, ICA was associated with increased grey matter volume in the right piriform cortex and decreased volume in the left orbitofrontal cortex. We further observed structural brain alterations in the medial orbital gyrus within the secondary olfactory cortex, in the middle frontal gyrus and in the medial occipital cortex. These data indicate that congenital olfactory deprivation likely affects the developing brain beyond the primary olfactory cortex.
Scientific articles, books, thesis etc.
Invited review: Karstensen HG and Tommerup N: Isolated and Syndromic forms of Congenital Anosmia (2012) Clinical Genetics; 81:210-215
Original article: Karstensen HG, Mang Y, Fark T, Hummel T, Tommerup N: The first mutation in isolated congenital anosmia: X-linked anosmia due to a CNGA2 mutation (2014). Human Mutation (in review)
Original article: Léa Gagnon, Martin Vestergaard, Kristoffer Madsen, Helena G Karstensen, Hartwig Siebner, Niels Tommerup, Ron Kupers, Maurice Ptito, Neural correlates of taste perception in congenital olfactory impairment, Neuropsychologia, Available online 29 July 2014, ISSN 0028-3932, http://dx.doi.org/10.1016/j.neuropsychologia.2014.07.018.
Thesis: Genetic and Phenotypic Studies of Isolated Congenital Anosmia and Hyposmia
European Human Genetics Conference, Amsterdam 2011
The Brain Prize Meeting 2013
PhD day, University of Copenhagen 2010-2013
Karstensen HG, Mang Y, Djurhuus B, Ellefsen B, Klausen C, Leffers AM, Siebner H, Eiberg H, Tommerup N: Search for the genetic cause of isolated congenital anosmia and hyposmia in an extended Faroese family (In preparation)
Karstensen HG, Vestergaard M, Baaré W, Jensen BV, Gagnon L, Djurhuus B, Ellefsen B, Klausen C, Leffers AM, Skimminge A, Tommerup N, Siebner HR. Olfactory depriviation shapes brain structure: a morphometric MRI study on a cohort with isolated congenital anosmia and hyposmia from the Faroe Islands. (In preparation)
Karstensen HG, Jensen BV, Baaré W, Ellefsen B, Djurhuus B, Tommerup N, Siebner H, Vestergaard M: Morphometric analysis of the oflactory sulcus in isolated congenital anosmia and hyposmia (In preparation).
Publications outside the scientific community, i.e. lectures, periodicals, articles in newspapers, television and radio
Lectures to 3rd semester medical students, University of Copenhagen
Presentation at Summer school on human olfaction 2011, Dresden Germany
Interview in Goðan morgun Føroyar October 31. 2011