Browsing by Subject "medicinsk genetik"

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  • Sandbacka, Maria (Helsingin yliopisto, 2013)
    Müllerian aplasia (MA) is a rare congenital disorder of the female reproductive tract. It involves loss of a functional uterus and upper two thirds of the vagina, resulting in infertility and need of treatment to enable normal sex life. Skeletal and renal structural abnormalities, such as scoliosis and renal agenesis are often associated with MA. The patients are otherwise healthy females with normal secondary sex characteristics and karyotype (46,XX). However, psychosocial problems are often encountered in MA patients because of its large impact on a woman s life. The incidence of MA is estimated to be at least 1:5000 newborn girls worldwide. The aim of this study was to decipher the complex genetics of MA in order to shed light on its underlying causes, which presently are unknown for the majority of the patients. For this purpose we utilized clinical data and DNA samples from a large cohort of Finnish MA patients, the second largest world-wide published to date. We used several genome-wide assays as well as gene-specific methods for studying copy number variations (CNVs), DNA methylation and for performing candidate gene and mutation screening. As a major finding we were able to link a new gene, the T-box gene TBX6 essential in mesodermal embryotic development, to MA. We found a splice site mutation in 2/112 (1.8%) patients and rare missense variants, which were significantly more common in patients than in controls. In addition, sequencing of LHX1 crucial in early reproductive duct development and previously associated to MA, revealed three missense mutations in 5/112 (4.4%) patients thereby strengthening its position in the development of MA. Additionally, nine CNVs were identified in 8/50 (16%) MA patients. Seven of these are novel found in only one patient each and therefore their relevance in MA cannot be concluded. However, genes within these CNVs are interesting for future candidate gene studies. Two CNVs, namely deletions in 16p11.2 including TBX6 and in 17q12 including LHX1 were found in 5/54 (9%) and 1/54 (2%) MA patients, respectively, supporting their importance in MA etiology. Interestingly, we identified four (3.4%) MA patients with a combination of TBX6 and LHX1 variants or a TBX6 variant and a CNV highlighting the complex genetics of MA. We could also show that occurrence of the Y-chromosomal gene TSPY1 and duplications of SHOX, both previously suggested as causative of MA in a small patient cohort, are not associated with MA in the Finnish patient cohort. Also hypomethylation of the regulatory domain H19 ICR1, was not observed in Finnish MA patients, although it was previously identified in a few syndromic patients with MA. The results of this study are important for understanding the regulation of the development of the female reproductive tract, which remains elusive. They are also important for a broader field of developmental medicine due to the common mesodermal origin of reproductive organs, kidneys and vertebrae.