High-Risk Genotypes Associated with Poor Response to Controlled Ovarian Stimulation in Indian Women.

Background: Infertility is a global burden and has become exceedingly common in the preceding years; controlled ovarian stimulation (COS) is a pre-requisite for couples opting to conceive via in vitro fertilisation (IVF). Based on the number of oocytes retrieved upon COS, a patient may be classified as a good responder or poor responder. The genetic aspect of response to COS has not been elucidated in the Indian population. Aims: This study aimed to establish a genomic basis for COS in IVF in the Indian population and to understand its predictive value. Settings and Design: The patient samples were collected at both Hegde Fertility Centre and GeneTech laboratory. The test was carried out at GeneTech, a diagnostic research laboratory based in Hyderabad, India. Patients with infertility without any history of polycystic ovary syndrome and hypogonadotropic hypogonadism were included in the study. Detailed clinical, medical and family history was obtained from patients. The controls had no history of secondary infertility or pregnancy losses. Materials and Methods: A total of 312 females were included in the study comprising 212 women with infertility and 100 controls. Next-generation sequencing technology was employed to sequence multiple genes associated with response to COS. Statistical Analysis Used: Statistical analysis using odds ratio was carried out to understand the significance of the results obtained. Results: Strong association of c.146G>T of AMH, c.622-6C>T of AMHR2, c.453-397T>C and c.975G>C of ESR1, c.2039G>A of FSHR and c.161+4491T>C of LHCGR with infertility and response to COS was established. Further, combined risk analysis was carried out to establish a predictive risk factor for patients with a combination of the genotypes of interest and biochemical parameters commonly considered during IVF procedures. Conclusion: This study has enabled the identification of potential markers pertaining to response to COS in the Indian population.

Genetic counseling for pre-implantation genetic testing of monogenic disorders (PGT-M).

Pre-implantation genetic testing (PGT) is a vital tool in preventing chromosomal aneuploidies and other genetic disorders including those that are monogenic in origin. It is performed on embryos created by intracytoplasmic sperm injection (ICSI). Genetic counseling in the area of assisted reproductive technology (ART) has also evolved along with PGT and is considered an essential and integral part of Reproductive Medicine. While PGT has the potential to prevent future progeny from being affected by genetic conditions, genetic counseling helps couples understand and adapt to the medical, psychological, familial and social implications of the genetic contribution to disease. Genetic counseling is particularly helpful for couples with recurrent miscarriages, advanced maternal age, a partner with a chromosome translocation or inversion, those in a consanguineous marriage, and those using donor gametes. Partners with a family history of genetic conditions including hereditary cancer, late onset neurological diseases and with a carrier status for monogenic disorders can benefit from genetic counseling when undergoing PGT for monogenic disorders (PGT-M). Genetic counseling for PGT is useful in cases of Mendelian disorders, autosomal dominant and recessive conditions and sex chromosome linked disorders and for the purposes of utilizing HLA matching technology for creating a savior sibling. It also helps in understanding the importance of PGT in cases of variants of uncertain significance (VUS) and variable penetrance. The possibilities and limitations are discussed in detail during the sessions of genetic counseling.

Genetic markers for inherited thrombophilia related pregnancy loss and implantation failure in Indian population - implications for diagnosis and clinical management.

AIM: The biology of recurrent pregnancy loss and recurrent implantation failure (RPL-RIF) is complex with multi-factorial etiology, with defective thrombosis being one of the most important and highly prevalent causes. The role of several thrombophilia related genes and variants associated with RPL-RIF is widely reported, and this study aimed to identify the risk associated with these genes in the Indian population. METHODS: Next generation sequencing (NGS) was employed for the current study. NGS enables sequencing of multiple genes, identification of new variants, and establishment of genetic correlations with reproductive failure in diverse population groups. The present NGS based study evaluates association of twenty-nine genotypes of ten coagulation pathway genes (F2, F5, F13, MTR, MTRR, MTHFR, ANXA5, PROZ, SERPINE1 and VEGFA) with RPL-RIF in 540 female subjects - 474 patients with early recurrent pregnancy loss, late pregnancy loss, pregnancy complications in late gestation and recurrent implantation failure, with 66 controls. RESULTS: The results emphasize inclusion of genotypes of seven thrombophilia genes (MTHFR, MTRR, MTR, ANXA5, PROZ, SERPINE1, VEGFA) for diagnosis of inherited thrombophilia risk for RPL-RIF in Indian population, as against the common practice of testing limited to F2, F5 and MTHFR genes. CONCLUSION: Deriving risk magnitude from Combined Risk Analysis and interpretation of high-risk haplotypes are crucial components for evidence based personalized management such as selection of drugs and dosage, and prenatal or pre-implantation recommendations, for high-risk patients in fertility and obstetric clinics.