Genetic Research in Fetal Medicine

Intracranial hemorrhage (ICH) is reported in premature infants and rarely, in prenatal life. Fetal ICH can be accurately identified in utero and categorized by antenatal sonography and/or MRI. Infectious disease, maternal drug exposure, alloimmune thrombocytopenia, maternal trauma, coagulation disorders and twin-to-twin transfusion syndrome can cause fetal ICH. However, in many cases, the cause is not identified and a genetic disorder should be taken into consideration. We conducted a review of the literature to investigate what we know about genetic origins of fetal ICH. We conducted targeted research on the databases PubMed and EMBASE, ranging from 1980 to 2020. We found 311 studies and 290 articles were excluded because they did not meet the inclusion criteria, and finally, 21 articles were considered relevant for this review. Hemostatic, protrombotic, collagen and X-linked GATA 1 genes were reported in the literature as causes of fetal ICH. In cases of ICH classified as idiopathic, possible underlying genetic causes should be accounted for and investigated. The identification of ICH genetic causes can guide the counselling process with respect to the recurrence risk, in addition to producing relevant clinical data to the neonatologist for the optimal management and prompt treatment of the newborn. Full article

In 1959, 63 years after the death of John Langdon Down, Jérôme Lejeune discovered trisomy 21 as the genetic reason for Down syndrome. Screening for Down syndrome has been applied since the 1960s by using maternal age as the risk parameter. Since then, several advances have been made. First trimester screening, combining maternal age, maternal serum parameters and ultrasound findings, emerged in the 1990s with a detection rate (DR) of around 90–95% and a false positive rate (FPR) of around 5%, also looking for trisomy 13 and 18. With the development of high-resolution ultrasound, around 50% of fetal anomalies are now detected in the first trimester. Non-invasive prenatal testing (NIPT) for trisomy 21, 13 and 18 is a highly efficient screening method and has been applied as a first-line or a contingent screening approach all over the world since 2012, in some countries without a systematic screening program. Concomitant with the rise in technology, the possibility of screening for other genetic conditions by analysis of cfDNA, such as sex chromosome anomalies (SCAs), rare autosomal anomalies (RATs) and microdeletions and duplications, is offered by different providers to an often not preselected population of pregnant women. Most of the research in the field is done by commercial providers, and some of the tests are on the market without validated data on test performance. This raises difficulties in the counseling process and makes it nearly impossible to obtain informed consent. In parallel with the advent of new screening technologies, an expansion of diagnostic methods has begun to be applied after invasive procedures. The karyotype has been the gold standard for decades. Chromosomal microarrays (CMAs) able to detect deletions and duplications on a submicroscopic level have replaced the conventional karyotyping in many countries. Sequencing methods such as whole exome sequencing (WES) and whole genome sequencing (WGS) tremendously amplify the diagnostic yield in fetuses with ultrasound anomalies. Full article

New technologies such as non-invasive prenatal testing (NIPT), capable of analyzing cell-free fetal DNA in the maternal bloodstream, have become increasingly widespread and available, which has in turn led to ethical and policy challenges that need addressing. NIPT is not yet a diagnostic tool, but can still provide information about fetal genetic characteristics (including sex) very early in pregnancy, and there is no denying that it offers valuable opportunities for pregnant women, particularly those at high risk of having a child with severe genetic disorders or seeking an alternative to invasive prenatal testing. Nonetheless, the ethical, legal and social implications (ELSI) include multiple aspects of informed decision-making, which can entail risks for the individual right to procreative autonomy, in addition to the potential threats posed by sex-selective termination of pregnancy (in light of the information about fetal sex within the first trimester), and the stigmatization and discrimination of disabled individuals. After taking such daunting challenges into account and addressing NIPT-related medicolegal complexities, the review’s authors highlight the need for an ethically and legally sustainable framework for the implementation of NIPT, which seems poised to become a diagnostic tool, as its scope is likely to broaden in the near future. Full article

The objective of our paper is to underline the importance of assessing microarray genetic analysis for the detection of chromosomal abnormalities in rare cases such as left atrial isomerism, mostly in the context of antenatally detected syndromes. We present the case of a 26-year-old primipara, at 26 weeks of gestation, with prior first trimester normal anomaly scan, who presented in our department accusing lower abdominal pain. An anomaly ultrasound examination of the fetus revealed cardiomegaly with increased size of the right atrium, non-visualization of the atrial septum or the foramen ovale, malalignment of the three-vessel view, location of the superior vena cava above the two-vessel view, slight pericardial effusion, and no interruption of the inferior vena cava nor presence of azygos vein being noted. Associated extracardiac abnormalities, such as small kidneys at the level of the iliac fossa, micrognathia, dolichocephaly with hypoplasia of the cerebellum, increased nuchal fold, and reduced fetal movements were also reported. A diagnostic amniocentesis was performed, and, while the conventional rapid prenatal diagnostic test of the multiplex quantitative fluorescent polymerase chain reaction (PCR) came as normal, the microarray analysis (ChAS, NCBI Built 37 hg 19, detection of microdeletions or microduplications larger than 100 kb) revealed two chromosomal abnormalities: a 22.84 Mb loss of genetic material in the 18q21.31–18q23 chromosomal region and a gain of 22.31 Mb of genetic material in the 20p13–20p11.21 chromosomal region. After the termination of pregnancy, a necropsy of the fetus was performed, confirming heterotaxy syndrome with a common atrium, no atrial septum, superior vena cava draining medianly, and pulmonary veins that drained into the lower segment of the left atrium due to an anatomically enlarged single common atrium. The extracardiac findings consisted of two bilobar lungs, dysmorphic facies, low-set ears, nuchal fold edema, and small kidneys located in the iliac fossa. These findings are conclusive evidence that left atrial isomerism is a more complex syndrome. The genetic tests of the parents did not reveal any translocations of chromosomes 18 and 20 when the Fluorescent in situ Hybridization (FISH) analysis was assessed. The antenatal detection of corroboration between different structural abnormalities using serial ultrasound examinations and cardiac abnormalities, together with the detection of the affected chromosomes, improves the genetic counseling regarding the prognosis of the fetus and the recurrence rate of the condition for siblings. Full article

Background: Intellectual developmental disorder with cardiac defects and dysmorphic facies (IDDCDF, MIM 618316) is a newly described disorder. It is characterized by global developmental delay, intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features. Biallelic pathogenic variants of TMEM94 are associated with IDDCDF. Methods and Results: In a prenatal setting, where fetal abnormalities were detected using antenatal sonography, we used trio-exome sequencing (trio-ES) in conjunction with chromosomal microarray analysis (CMA) to identify two novel homozygous loss of function variants in the TMEM94 gene (c.606dupG and c.2729-2A>G) in two unrelated Saudi Arabian families. Conclusions: This study provides confirmation that TMEM94 variants may cause IDDCDF. For the first time we describe the pathogenicity of TMEM94 defects detected during the prenatal period. Full article

Background: Congenital disorder of glycosylation (CDG) is a severe morphogenic and metabolic disorder that affects all of the systems of organs and is caused by a mutation of the gene PMM2, having a mortality rate of 20% during the first months of life. Results: Here we report the outcome of an in vitro fertilisation (IVF) cycle associated with preimplantation genetic testing for monogenic diseases (PGT-M) in a Romanian carrier couple for CDG type Ia with distinct mutations of the PMM2 gene. The embryonic biopsy was performed on day five of the blastocyst stage for six embryos. The amplification of the whole genome had been realized by using the PicoPLEX WGA kit. Using the Array Comparative Genomic Hybridisation technique, we detected both euploid and aneuploid embryos. The identification of the PMM2 mutation on exon 5 and exon 6 was performed for the euploid embryos through Sanger Sequencing with specific primers on ABI 3500. Of the six embryos tested, only three were euploid. One had compound heterozygosity and the remaining two were simple heterozygotes. Conclusion: PGT-M should be strongly considered for optimising embryo selection in partners with single-gene mutations in order to prevent transmission to the offspring. Full article