It is estimated that around 10–15% of the population have problems achieving a pregnancy. New innovations in the medical field have paved the way for millions of infertile couples to become parents. Medical advances have also made it possible to deliver a healthy baby without the risk of a genetic condition. One of the global health priorities is prevention of congenital anomalies. Genetics plays an important role in the pathogenesis of congenital anomalies.
Statistics suggest that genetic diagnosis is one of the main aspects of preventive medicine approach in developed countries. With modernization and technological advancement, a drastic shift from the traditional non-molecular visual microscope-based techniques (i.e., fluorescence in situ hybridization (FISH) or G-banding karyotype), to the latest molecular high-throughput techniques such as next-generation sequencing (NGS) has been witnessed. Genome-wide technologies are applied along the different stages of the reproductive health lifecycle from preconception carrier screening and pre-implantation genetic testing, to prenatal and postnatal testing.
Couples often assess their reproductive potential without acknowledging the reproductive roulette of the risk for an associated genetic disease. Newly available research and advanced technologies has led to a good progress in the pre-conception care field.
Genetic analysis can be implemented at any stage of the reproductive journey, starting from preconception to detect genetic carriers of frequent diseases like cystic fibrosis, haemophilia or fragile X syndrome; pre-implantation to ensure a chromosomal and genetically normal embryo is transferred, decreasing the risk of monogenetic disease or structural diseases; prenatal diagnosis etc. Lastly, it can be utilized to perform new born screening of common and actionable diseases, personalized genetic analyses such as single gene analysis for monogenic diseases and genetic panels or whole-exome sequencing for complex or clinically unspecific diseases.
Various researches say that most genetic disorders that result in sterility or child death are caused by recessive mutations which can also cause devastating diseases like cystic fibrosis when the patient carries both copies of the mutation. Currently, there are many genetic tests that assess the “mutational state” of a patient or a couple to reduce the probability of having a baby with a genetic disorder.
Pre-Implantation Diagnosis: This stage is summed up by detecting common reproductive risks or problems that hinders parenting. In other words, it tests if an embryo is aneuploid or not which is a common genetic abnormality accounting for approximately 50% of miscarriages.
PGS is also called aneuploidy screening that allows us to detect embryos affected by a known monogenic disorder that has been previously detected in parents. Besides, genetic disorders caused by gene mutations, variations other genetic conditions can have an impact on fertility, pregnancy, parents and new-born.
More than half of the embryos produced by in vitro fertilization (IVF) are aneuploids. The process of detecting numeric or structural chromosomal abnormalities for the purpose of embryo selection is generally referred to as pre-implantation genetic testing for aneuploidies (PGT-A), introduced in the 2000s. In recent years, PGT-A using FISH screening has been initially replaced by comprehensive approaches, including comparative genomic hybridization arrays (CGH) or single nucleotide polymorphism microarrays, and more recently, by next-generation sequencing (NGS)-based techniques. Currently, embryo biopsy is required for PGT-A testing. In the event of a poor blastocyst quality at biopsy, new effective approaches involving the sequencing of DNA (cell free DNA) secreted into the culture medium from the human blastocyst have been developed. In addition, PGT-A could mitigate the potential adverse effects associated with embryo biopsy.
Prenatal Diagnostics: It refers to a screening process to evaluate whether a foetus is at risk for various disabilities or diseases. The non-invasive prenatal test (NIPT) that is a genomics-based test is an ideal alternative to the conventional karyotype as a first-tier test in unselected populations of pregnant women undergoing aneuploidy screening or as a second-tier test in pregnant women considered to be high risk after first-tier screening for common foetal aneuploidies. The question is not whether noninvasive genome sequencing should be performed, but how to optimally implement it. Cell-free ‘fetal’ DNA is a by-product of trophoblast turnover and apoptosis that is found in maternal blood. Bioinformatics analysis parses out the maternal and fetal genomes and calculates a fetal fraction (the ratio of cell-free fetal DNA to maternal DNA). The fetal fraction is an important quality metric of prenatal screening; with larger fetal fractions leading to more accurate test results. There can also be large variations in fetal fractions. This variation is found over gestational age, in cases with fetal abnormalities, and it varies some with maternal characteristics such as obesity. Fetal fraction is relatively stable during the first and second trimesters and increases afterwards, going up faster in women who deliver preterm. Variation in fetal fraction is not completely understood, and it could potentially reflect placental function/health. Cell-free fetal DNA analysis may also reveal issues when there are maternal secondary findings, such as copy number variations (CNVs) and malignancies in the mother, both of which can affect the outcome of the pregnancy. The mechanism of where cell-free fetal DNA comes from is becoming increasingly important. It’s clear that this DNA comes from trophoblast cells and can be detected as early as 7 weeks after implantation. Studying clinical utility for prenatal tests is very important. It’s also important to understand the clinical utility from the patient’s perspective.
Some of the clinical features of these monogenic disorders, especially those associated with syndromic forms, can be identified throughout pregnancy by ultrasonography analyses. In these cases, and depending on the clinical impression, specific tests can be used to analyse certain genes or variants, as well as more complex and nonspecific technologies, such as CMA, NGS gene panels or whole Exome sequencing (WES), when a precise clinical guidance is not possible. Until now, products of conception (POC) studies have been carried out however, while using these techniques, the incidence of chromosomal abnormalities in miscarriages in the general population ranges between 40% and 80%, depending on the culture methods adopted.
Given this, new genomic technologies are positioning themselves as the first-choice technologies for the analysis of miscarriages and POC. Whole Exome sequencing (WES) is very useful for the detection of alterations in the sequence of any gene that may be related to the potential genetic condition even when clinical assessment is not possible but also, the optimization of bioinformatics analyses, making possible the identification of copy-number variations in these cases.
New-born Screening and Neonatal Care: Neonatal screening allows us to detect a wide number of genetic disorders, causing health problems starting in infancy or early childhood, mainly metabolic disorders like phenylketonuria. Early detection and treatment can help prevent inborn errors of metabolism, intellectual and physical disabilities and life-threatening illnesses during the first few hours of life. Monogenic diseases have a high impact in the neonatal morbi-mortality, accounting for 20% of infant deaths and 18% of paediatric hospitalizations. Genomic testing of these patients aims to provide a comprehensive molecular diagnosis that allows for early intervention of the patient and proper genetic counselling of the family in order to reduce the time spent in the diagnostic odyssey.
NGS technologies, especially introduction of the WES, has become a turning point in rare genetic diseases research. It has allowed development and implementation of strategies to uncover the mechanisms behind all rare diseases to sketch a “molecular atlas” showing links between molecular genetic profiles and states of health or disease.
Whole exome sequencing (WES) and whole genome sequencing (WGS) are the most recent technologies based on NGS that are developed for genomic diagnostic purposes when a genetic disorder for which single-gene or limited gene testing fails to provide a genetic explanation.
Currently, NGS-based tools can point to the implication of a single gene (or a small number of genes) and help establish a rapid diagnosis in just a few weeks or even less in a large percentage of cases.
In conclusion it can be said that recent advances in reproductive genomics is a fast growing field from basic and translational point of view. However, recent developments in new sequencing technologies have made it possible to compact one or more tests into a single NGS-based analysis, thus reducing diagnostic costs and time. The general state of health in the reproductive environment is gaining increasing attention and clinical relevance. Medicine is undergoing an important transformation from a reactive to a preventive approach: the future will focus on the integrated diagnosis, treatment and prevention of diseases in individual patients.
Agilus Diagnostics, a subsidiary of Fortis Healthcare Limited
