Year: 2014
Type: dissertation
Study design: Observational Study
Abstract: Diseases can occur due to genetic changes that alter the normal function of genes. These alterations may be either inherited or acquired somatically during lifetime. Aims of this thesis work were to efficiently analyze large quantities of epidemiological and molecular data, and to characterize new susceptibility conditions and genetic causes of human diseases. First, genetic basis of right atrial isomerism (RAI) was studied in a Finnish family with five affected siblings and healthy parents. RAI is a heterotaxy syndrome with disturbances in the left-right axis development resulting in anomalies in heart and other asymmetrical organs. Linkage analysis and candidate-gene approach followed by sequencing revealed two truncating mutations in GDF1 segregating with RAI in an autosomal recessive manner. This finding, supported by the similar phenotype of laterality defects in Gdf1 knockout mice, provides evidence that RAI can be recessively inherited with GDF1 as the causative gene. Second, six patients with severe intellectual disability (ID) of unknown etiology were studied by genetic mapping and whole-genome sequencing (WGS) analysis. Autosomal recessive inheritance of severe ID was confirmed by extensive genealogy, and by linkage analysis showing high statistical significance for a homozygous region at 3p22.1-3p21.1. Three genes, TKT, P4HTM and USP4, with potentially protein damaging sequence changes were identified within the locus. The variants were rare and present only in heterozygous form in population-matched controls. This study facilitates clinical and molecular diagnosis of similar patients and further research on the role of the genes in the development of severe ID. Third, we performed WGS and transcriptome profiling of 38 uterine leiomyomas and corresponding myometrium from 30 women. Uterine leiomyomas are benign tumors that affect approximately three-quarters of women and may cause severe symptoms including abdominal pain and excessive uterine bleeding. Abundant complex chromosomal rearrangement events resembling the recently described chromothripsis phenomenon were detected. The events had created leiomyoma-specific driver changes, and occurred sequentially in some tumors. Four molecular pathways driven by alterations of MED12, FH, HMGA2/HMGA1 or COL4A5/COL4A6 were identified. The clonal origin of multiple separate tumors was also proven. The molecular genetic characterization of uterine leiomyomas will hopefully lead to better understanding of tumor growth and personalized treatment of patients. Fourth, a systematic search for familial aggregation of all tumor types was performed to identify new susceptibility phenotypes. We employed the entire population based data in the Finnish Cancer Registry and clustered 878,593 patients according to family name at birth, municipality of birth and tumor type. The rate of familial occurrence was estimated with a cluster score method. Among known cancer predisposition syndromes, Kaposi sarcoma (KS) with largely unknown genetic background was highlighted. Population records verified majority of the clustered KS patients as true relatives, providing further evidence that the clustering works well in estimating familiality. This study enabled identification of families suitable for a succeeding research on genetic basis of novel tumor predisposition phenotypes.
Source: Työväentutkimus Vuosikirja
Author: Eevi Kaasinen
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1502869829