# Invasive Prenatal Diagnostics: A Cornerstone of Perinatal Management
## 2 Techniques of Invasive Diagnostics
### Amniocentesis
#### 2.1.1 Genetic Analysis
The resolution of an array of comparative genomic hybridisation has evolved throughout the years; currently, the theoretical peak resolution is 1-3 kilobases [73]. It is important to note that advanced, non-invasive prenatal screening lacks the capacity to identify microdepletions and microdeplications as effectively as array CGH performed on chorionic villi or amniotic fluid cells. Having access to foetal cell material with the means of CVS or amniocentesis is therefore preferred over non-invasive screening methods if the main goal is the detection of microdeletion and microduplication disorders [74]. A large study by [PERSON] et al. [75] was the first to demonstrate the usefulness of CGH in prenatal diagnosis and its superiority over traditional karyotyping. Among over 5000 analysed cases, the overall detection rate of clinically significant CNVs was 5.3%, which increased to 6.5% in cases with abnormal ultrasonographic findings. Moreover, 71% of the reported abnormalities were <10 Mb and were not expected to be identified by conventional karyotyping. A prospective cohort study published in 2013 by [PERSON] et al. [76] presented an excess detection rate of abnormalities by CGH of 4.1% over conventional karyotyping among patients with abnormal foetal ultrasonographic findings. In subsequent years, the utility of CGH has been repeatedly proven by many studies [77; 78; 79; 80]. However, the diagnostic yield depends on the targeted population. In a group of high-risk pregnancies with common aneuploidies excluded with rapid PCR tests, [PERSON] et al. [81] demonstrated that the overall diagnostic yield of CGH was 15.1% and increased to 20% in the case of multiple structural anomalies. It was lowest in samples taken because of isolated foetal growth restriction and abnormal FTS only (5.7%). According to [PERSON] et al. [82], the diagnostic yield was lowest among foetuses with isolated increased much translucency and common trisomies excluded (2.7%). However, even in this group of patients, a significant number of pathogenic CNVs were detected. Therefore, CGH is considered to be a standard prenatal diagnostic tool in many countries. _Next-Generation Sequencing_--While the introduction of comparative genomic arrays has undoubtedly revolutionised the field of genetic diagnostics, next-generation sequencing is a true achievement of modern genomics. It uses a wide range of tools to read and analyse a whole sequence of the examined genome [83]. With this method, it is feasible to detect single nucleotide variants (SNVs). _Whole-exome sequencing (WES)_ is used to detect point mutations and small insertions-deletions within coding sequences. It reaches an unprecedented resolution. However, its utility for detecting CNVs is limited [84]. On the other hand, _whole-genome sequencing (WGS)_ enables an analysis of both coding and non-coding sequences. With this feature, WGS is expected to outperform WES both in SNV and CNV detection [85; 86]. Despite currently being the most advanced method of genomic examination, it is still underused as a first-tier tool. The probable reason for this is a lack of population reference maps of structural variations in national biobanks [87], which impedes clinical interpretation. Recently, it has been suggested that a combination of tools relying on different signal types would increase examination performance [87; 88; 89]. Even though the sequencing of protein-coding regions of genes plays an important role in postnatal diagnosis, its diagnostic yield of prenatal diagnosis is yet to be defined. Most recent studies have examined the detection rate of WES in cases of foetal structural abnormalities and normal karyotyping and CGH. The results vary greatly from 9.1% to 45.9% [90; 91; 92; 93]. This is probably because of small cohort bias and a major discordance among the genetic causes of different structural anomalies. In 2024, [PERSON] et al. [94] classified foetal structural anomalies into seven categories, according to the impaired system.