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Browsing by Subject "whole exome sequencing"

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  • Exome sequencing reveals a novel disease-causing gene in a Finnish family 
    Karhu, Thomas (2016)
    The main focus of this study is a Finnish family, in which four out of eight children presented with an unidentified disease causing a grave developmental disorder. A genetic cause for this disorder was sought by utilizing whole exome sequencing. Both parents, two affected siblings and one healthy sibling were sequenced. After variant filtering and analysis, only the candidate gene UBA5 passed the filtering criteria. The results were validated using Sanger sequencing. Both affected individuals were shown to have compound heterozygous variants of this gene, with one of the variants being novel. No cases of disease in humans associated with UBA5 have prior to this study been reported. However, other unrelated patients with a similar phenotype have since been found to possess pathogenic variants in the gene UBA5, which confirms the claim that it's the disease-causing gene. Therefore, this study enhances our knowledge of the gene's physiological significance.
  • Identification of disease mutations in early-onset neuropathies by whole exome sequencing 
    Pöyhönen, Julia Rosanna Hellin (2013)
    Charcot-Marie-Tooth (CMT) neuropathy is phenotypically and genetically a very heterogeneous disease. It can be inherited as an autosomal recessive, dominant or X-linked trait. CMT is characterized by distal muscle weakness, atrophy and deformity of the feet as well as clumsiness of gait. The onset of CMT varies and also the symptoms of the disease can vary even among the members of a single family. So far more than 40 genes have been identified for CMT and the list is estimated to grow by 30-50 genes. Whole exome sequencing (WES) is a new next generation sequencing technique, which targets the protein-coding area of the genome. Through WES analysis it is possible to search for disease causing mutations with all kinds of inheritance patterns. Patients suffering from CMT are good candidates for WES analysis because of the genetic heterogeneity of their disease. WES can be used for diagnosing Mendelian disorders with atypical symptoms as well as diseases, which are difficult to confirm using clinical criteria alone and which require costly evaluation, e.g. CMT. In this master study new disease causing mutations for early-onset neuropathies are identified by whole exome sequencing (WES). The aims of this study include using WES for the molecular diagnosis of four patients suffering from early-onset axonal neuropathies, the functional analysis of possible causative variants and improving and developing the process of analyzing variants from whole exome sequencing data, especially the analyzing steps of insertion and deletion variants. Finding causative variants among the insertion and deletion variants has previously been often left out from the WES analysis because of the lack of systematic analysis technique. As a result of the WES data analysis a new candidate disease gene, tripartite motif containing 2 (TRIM2) was identified. A missense mutation c.761T>A (p.E254V) and a deletion c.1779delA (p.K594Rfs7X) were found in patient 2, who suffers from severe CMT type 2. The carrier frequency was analysed to see whether the variants are present in the general population or not. The functional analysis of TRIM2 was started by preparing constructs carrying the missense mutation and the deletion and by setting up conditions for western blotting.
  • Krooninen myeloinen leukemia ja hankinnaisten mutaatioiden kartoittaminen koko eksomi sekvensoinnilla 
    Eskelinen, Jaakko (2016)
    Kroonisen myeloisen leukemian molekyyligeneettiset mekanismit taudin syntyyn tunnetaan hyvin.Tarkempia taudin etenemiseen liittyviä geneettisiä muutoksia ja taudin kehittymiseen liittyviä lääkeresistansseja tunnetaan vain osittain. Tutkimuksessa neljän potilaan koko genomin eksomi sekvensoitiin. Sekvensointi datasta valittiin mutaatioita, joiden ajateltiin mahdollisesti liittyvän taudin kulkuun ja progressioon. Valitut mutaatiot seulottiin Sanger-sekvensoinnilla 65:ltä kroonista myeloista leukemiaa sairastavalta potilaalta. Tutkimuksen hypoteesina oli, että suuri leukemiakantasolumäärä voi kertoa myös taudin aggressiivisemmasta biologiasta ja liittyä mahdollisesti lisääntyneeseen määrään muita geneettisiä poikkeavuuksia. Tutkimuksen tarkoituksena oli selvittää mutaatioiden määrää ja laatua kroonisen vaiheen potilailla. Tutkimuksessa potilailta löydettiin yksittäisiä hankinnaisia mutaatiota, jotka voitiin varmistaa Sangersekvensoinnin avulla, mutta laajemmasta 65 potilaan validaatiojoukosta mutaatioita ei seulonnalla löydetty. Tutkimuksen perusteella seulotut mutaatiot eivät ole yleisiä KML potilailla.

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