Gynecology and Reproduction: Genomics for personalized medicine

The field of gynaecology and reproduction offer enormous opportunity for personalized medicine implementation. The topic of the proposed research programme is focused on major health issues in this area. Subfertility affects 10-12% of reproductive-aged couples worldwide. About 6% of total births worldwide are born with a serious congenital disorder while up to 70% of congenital disorders could either be prevented or affected children could otherwise be offered care that could be life-saving or reduce the severity of the disability. On the other hand, urinary incontinence in women has an estimated prevalence of 30% and significantly affects healthy ageing and is increasing in prevalence.  In up to 40% of subfertile men, no etiologic diagnosis can be made. Therefore, we plan to comprehensively estimate the contribution of genetic factors in male infertility by the combination of molecular karyotyping, whole exome sequencing (WES) and global gene expression analysis in testis. While several genetic, maternal and environmental factors are known to cause congenital anomalies, approximately 50% of all congenital anomalies cannot be linked to a specific cause. We will use WES to comprehensively estimate the contribution of known developmental genes and to identify potential new ones as causative in congenital anomalies. Furthermore, we will systematically analyse human genetic diseases in terms of severity and childhood occurrence to design gene panels which could be used for preconceptional (recessive genetic diseases) and prenatal (recessive and dominant) genomic screening and consequently primary prevention of genetic diseases. Several factors, including those related to the blastocyst and endometrial receptivity, are contributing to the success of the ART procedures. We, therefore, plan to use WES, global gene expression analysis (transcriptomics)  to identify potential biomarkers, important for prioritisation of embryos - suitable for transfer in ART procedures. Additionally, we plan to identify specific gene expression signatures specific for endometrium in women with PCOS and increased weight as well as in women with uterine fibroids.  Genetic contribution to urinary incontinence in women is still largely unknown. The objective of this part of the program is to evaluate the rate of familial occurrence/clustering of urinary incontinence and to identify genes involved in genetic predisposition in familial cases with whole exome sequencing (WES). In conclusion, we will employ novel genomic technologies to contribute original data in terms of genetic aetiology and biomarkers in several most prominent health challenges in the area of gynaecology and reproduction. Consequently, we will contribute to the development of personalized medicine in the field.

We will contribute original data on the impact of genetic factors in several pathologies related to reproduction and gynecology: - the role of copy number variants (CNVs) and gene mutations in male infertility will be investigated. Findings have potential implication for understanding of male infertility etiology and routine management of subfertile men in the clinic, - potential novel gene candidates and mechanisms involved in male infertility will identified global analysis of gene expression - we will contribute original, comprehensive evaluation of genetic mutations and potentially identify new genes and mechanisms associated with congenital anomalies. Results will be directly usable in routine diagnosis and prevention of congenital anomalies  - we will design original panel of genes which could be used for preconceptional and prenatal genomic screening. Both panels will the basis to provide personalized medicine solution to couples in terms of prevention of severe prenatal, neonatal and childhood disorders. - we will contribute to identification of potential transcriptomic biomarkers which could be used for embryo prioritisation in ART procedures. If biomarker would demonstrate sufficient predictive power, it could be used by itself or in combination with other predictors for improvement of ART procedures.  - we will investigate the potential of transcriptomic biomarkers for endometrial receptivity in PCOS/obesity and in uterine fibroids. If biomarker would demonstrate sufficient predictive power, it could be used by itself or in combination with other predictors for improvement of ART procedures. - we will evaluate the contribution of family history as risk factor for urine incontinence in women and identify potential genes and mechanisms involved in the pathogenesis. Results could potential serve in clinical setting to identify a subgroup of women with high genetic risk for urine incontinence.

We will develop genomic tools for personalised medicine in the area of reproduction and gynecology. While some of the results have potential to be offered in the context of routine diagnostic genetic services, others (i.e. genomic screenings) could be used commercially on the basis of participatory medicine. The program has the potential to contribute to both, improved public health services and to genomic tests which could be used on the basis of commercial participatory personalized medicine.