Many genetic disorders are detectable in the prenatal period, and the capacity to identify them has increased remarkably as molecular genetic testing techniques continue to improve and become incorporated into clinical practice. The indications for prenatal genetic testing vary widely, including follow-up of an anomaly found by routine ultrasound or maternal aneuploidy screening, a family history of genetic disease, advanced maternal or paternal age, or evaluation of a low-risk pregnancy due to parental concern. The interpretation of genetic variants identified in the prenatal period poses unique challenges due to the lack of ability for deep phenotyping as well as the option to make critical decisions regarding pregnancy continuation and perinatal management. In this review, we address the various modalities currently available and commonly used for genetic testing, including preimplantation genetic testing of embryos, cell-free DNA testing, and diagnostic procedures such as chorionic villous sampling, amniocentesis, or percutaneous umbilical blood sampling, from which samples may be sent for a wide variety of genetic tests. We discuss the difference between these modalities for the genetic diagnosis of a fetus, their strengths and weaknesses, and strategies for their optimal use in order to direct perinatal care.

Genetic diagnosis in the fetus.

Advances in prenatal/neonatal genetic screening practices and next generation sequencing (NGS) technologies have made the detection of molecular causes of pediatric diseases increasingly more affordable, accessible, and rapid in return of results. In the past, families searching for answers often required diagnostic journeys leading to delays in targeted care and missed diagnoses. Non-invasive prenatal NGS is now used routinely in pregnancy, significantly altering the obstetric approach to early screening and evaluation of fetal anomalies. Similarly, exome sequencing (ES) and genome sequencing (GS) were once only available for research but are now used in patient care, impacting neonatal care and the field of neonatology as a whole. In this review we will summarize the growing body of literature on the role of ES/GS in prenatal/neonatal care, specifically in neonatal intensive care units (NICU), and the molecular diagnostic yield. Furthermore, we will discuss the impact of advances in genetic testing in prenatal/neonatal care and discuss challenges faced by clinicians and families. Clinical application of NGS has come with many challenges in counseling families on interpretation of diagnostic results and incidental findings, as well as re-interpretation of prior genetic test results. How genetic results may influence medical decision-making is highly nuanced and needs further study. The ethics of parental consent and disclosure of genetic conditions with limited therapeutic options continue to be debated in the medical genetics community. While these questions remain unanswered, the benefits of a standardized approach to genetic testing in the NICU will be highlighted by two case vignettes.

/pdf/challenges-in-the-clinical-understanding-of-genetic-testing-1peb179e.pdf

Challenges in the clinical understanding of genetic testing in birth defects and pediatric diseases

Noninvasive cfDNA testing for monogenic disorders (sgNIPT) has become integrated into the care of pregnant women at increased risk based on carrier status, known family history, or ultrasound anomalies. The availability of commercial tests for common autosomal recessive and de novo autosomal dominant conditions has led to the use of these tests in low-risk pregnancies. However, is the technology ready for use in this low-risk population? This report is a summary of the debate on this topic at the 27th International Conference on Prenatal Diagnosis and Therapy. Both expert debaters provided strong arguments in favor and against the use of sgNIPT in low-risk pregnancies. The argument in favor of sgNIPT for autosomal recessive conditions is that it allows the identification of affected pregnancies without the need for involving the partner in testing. Arguments for sgNIPT for autosomal dominant conditions include identification of affected fetuses that would have either presented later in pregnancy with fetal anomalies or not been detected prenatally given normal ultrasounds, respect for patient autonomy and patient desire for information. Strong arguments were made against offering sgNIPT screening. Given that traditional carrier screening for recessive conditions can be carried out in many jurisdictions, the added value of sgNIPT has not been clearly demonstrated. Arguments against sgNIPT for autosomal dominant conditions included the total lack of clinical validation studies and the risk of false reassurance in cases of negative results and unnecessary invasive procedures in cases of false positive results. Although there is a desire to take advantage of new technologies to improve the detection of monogenic disorders in low-risk populations, based on the discussion and the audience vote, it appears premature to offer sgNIPT to all low risk pregnant women. Further clinical validation studies are needed prior to broad implementation.

Current controversy in prenatal diagnosis: The use of cfDNA to screen for monogenic conditions in low risk populations is ready for clinical use.

Background: Apert, Pfeifer and Crouzon syndromes are autosomal dominant diseases characterized by craniosynostosis. They are paternal age effect disorders. The association of paternal age with the Beare-Stevenson syndrome (BSS), one of the most rare and severe craniosynostosis, has been uncertain. Gain-of-function mutations in FGFR2 have been described as the cause for these syndromes, which arise in the male germline evolving through a mechanism involving spermatogonial clonal expansion. Case report: Here we describe a child affected with BSS, whose father was 36 years old and had Congenital Bilateral Absence of the Vas Deferens (CBAVD). The child was heterozygous for the pathogenic variant FGFR2 p.Tyr375Cys. By reviewing the literature, we found BSS fathers are older than BSS mothers (mean age in years: 39 ±10 vs 30 ±6, p=0.006). Male age greater than 34 years and CBAVD are both factors associated with poor spermogram parameters, which may represent an additional selective pressure to sperm carrying FGFR2 gain-of-function mutations. Conclusion: These findings are consistent with the hypothesis that BSS is a paternal-origin genetic disorder. Further experimental studies would be needed to confirm this hypothesis.

/pdf/report-of-a-father-with-congenital-bilateral-absence-of-the-6znyblmg2z.pdf

Report of a Father With Congenital Bilateral Absence of the Vas Deferens Fathering a Child With Beare-Stevenson Syndrome.

A major challenge for cell-based non-invasive prenatal testing (NIPT) is to distinguish individual presumptive fetal cells from maternal cells in female pregnancies. We have sought a rapid, robust, versatile, and low-cost next-generation sequencing method to facilitate this process. Toward this goal, single isolated cells underwent whole genome amplification prior to genotyping. Multiple highly polymorphic genomic regions (including HLA-A and HLA-B) with 10-20 very informative single nucleotide polymorphisms (SNPs) within a 200 bp interval were amplified with a modified method based on other publications. To enhance the power of cell identification, approximately 40 Human Identification SNP (Applied Biosystems) test amplicons were also utilized. This method allowed reliable differentiation of fetal and maternal cells. In fully informative cases, two haplotypes were found within the maternal reads, and fetal cells showed reads with one but not the second maternal haplotype while also showing a novel paternal haplotype absent in the mother. For SNP typing, at least 2 SNPs and 10% of informative SNPs were required to differentiate a fetal cell from a maternal cell. A paternal DNA sample is not required using this method. The assay also successfully detected point mutations causing Tay Sachs disease, cystic fibrosis, and hemoglobinopathies in single lymphoblastoid cells, and monogenic disease-causing mutations in three cell-based NIPT cases. This method could be applicable for any monogenic diagnosis.

/pdf/use-of-amplicon-based-sequencing-for-testing-fetal-identity-4cjbqm21if.pdf

Use of amplicon-based sequencing for testing fetal identity and monogenic traits with single circulating trophoblast (SCT) prenatal diagnosis

Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders using circulating cell-free fetal DNA

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Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders using circulating cell-free fetal DNA