Prenatal testing for neuropsychiatric disorders

Why a special topic issue on prenatal testing for neuropsychiatric disorders, and why now? The relevance of intrauterine exposures in the genesis of neuropsychiatric morbidities has only recently come to the attention of investigators in the field. Maternal obesity is now well known to be associated with an increased risk of autism spectrum disorders, schizophrenia, attention deficit hyperactivity disorder, anxiety and depression, and impairment in cognition in offspring. A causal association is supported by evidence from epidemiologic studies, animal models, and biologic plausibility, with relevant pathways and networks being elucidated. Similarly, the severity of maternal gestational diabetes has been associated with the likelihood of developing neuropsychiatric morbidity in the child. From a genetic standpoint, recent advances in genomics (including microarrays, exome sequencing, and genome-wide association studies) have shown that mutations and variants in genes involved in neurodevelopment may result in different clinical manifestations and gradients of severity, including attention deficit hyperactivity disorder, autism spectrum disorders, and schizophrenia. Such disorders have a complex genetic architecture that does not follow typical patterns of Mendelian inheritance. The odds and severity of clinical sequelae in parents and offspring depend on the size of the DNA sequence variations, the number of genes involved (polygenic basis), and their diverse disruptive effects on postsynaptic proteins involved in neurodevelopmental processes. While it is too early to establish how the insights gained from such basic research may affect prenatal screening and diagnosis, the implications of genes with established effects on neuropsychiatric health impact prenatal care. The relatively recent increase in the prevalence of neuropsychiatric conditions requires that all practitioners involved in prenatal diagnosis be familiar with the main issues involved. Furthermore, as a result of the uptake of noninvasive prenatal screening using cell-free DNA, prenatal diagnostic procedures (and, by implication, chromosome microarray testing) have significantly decreased. This issue was conceived to start a discussion on the current benefits and limitations of prenatal testing for neuropsychiatric conditions, keeping in mind what might be missed if cell-free DNA analysis only focused on the common autosomal trisomies (e.g. 13, 18, and 21). Genetic counselors are often at the forefront in the care of pregnant women with a personal or family history of neuropsychiatric disorders. Yet, not all counselors feel prepared to deal with a family history of neuropsychiatric disease. As outlined in the paper by Inglis and colleagues, a comprehensive approach is required to not only provide an estimate regarding the probability for the offspring to develop the condition but also to explore the patient’s expectations and needs and to provide an individualized framework and support in cases of mental illness with a risk of suicide. Chromosome microarray testing (CMA) is currently the gold standard for fetuses detected with structural central nervous system abnormalities. When CMA testing is offered to pregnant women without a specific clinical indication, it carries the potential (in about 1% to 3% of cases) of detecting susceptibility loci for neurodevelopmental disorders. How should providers communicate such incidental findings, and how expectant couples process and are affected by such information in their decision-making has not yet been completely investigated. In this issue, the findings in a Dutch cohort are presented, in which the diagnosis of neurodevelopmental susceptibility loci was reported to the parents. Expert post-test genetic counseling allowed the couples to translate such information into prenatal and postnatal action. DiGeorge syndrome, which can be associated with a 22q11.2 deletion, has significant neuropsychiatric manifestations. Several genes are present within the typically deleted region, and despite high penetrance, there is variable expressivity. This is responsible for the differential clinical effects in multiple organ systems. As outlined in the article by Dugoff et al., although cell-free DNA testing offers the possibility to screen pregnant women for the typical 3.0-Mb deletion responsible for most of the clinical phenotype, it does not currently meet the requirements for large-scale screening tests. Its routine clinical implementation is not recommended by several professional societies (International Society for Prenatal Diagnosis and American College of Obstetrician and