Symposium: neonatology
Genetic and genomic investigations in the neonatal intensive care unit

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Abstract

Genetic testing is available and widely used in the neonatal intensive care setting for a broad range of complex presentations arising both antenatally and in the postnatal period. Here we discuss the investigations currently available to clinicians in the neonatal intensive care unit, such as array comparative genomic hybridization (aCGH), FISH (fluorescent in situ hybridization) and quantitative florescent polymerase chain reaction (QF-PCR), later looking to the future of clinical genomic testing, in the form of next generation sequencing panels (NGS panels), whole exome (WE) and whole genome (WG) sequencing. The mainstreaming of genetic medicine requires non-genetic specialists, such as neonatologists and paediatricians, to have confidence and knowledge of the testing process, the technologies available and the ethical and social considerations associated with their use.

Introduction

Genetic testing is widely used in the neonatal intensive care setting for a broad range of complex presentations identified antenatally and in the postnatal period. The mainstreaming of genetic medicine requires non-genetic specialists, such as neonatologists and paediatricians, to have confidence initiating and managing the testing process, including knowledge of the technologies available and the ethical and social considerations associated with their use.

Antenatally, genetic technologies can be used in conjunction with IVF (in-vitro fertilization) where there is a known familial risk of genetic disease through pre-implantation genetic diagnosis (PGD), providing the opportunity to prevent genetic disease in offspring. During pregnancy, concerns raised during routine antenatal screening – such as high aneuploidy risk or concerns from ultrasound scanning – may lead to genetic tests being undertaken – either as karyotyping or array comparative genomic hybridization of fetal DNA samples (from amniocentesis or chorionic villous sampling), or through non-invasive techniques such as the analysis of free fetal DNA in maternal blood (non-invasive prenatal testing, or NIPT).

Section snippets

Postnatal testing

Most genetic tests are undertaken for three main purposes. Diagnostic testing is undertaken when there is a phenotype suggestive of a genetic disease. This could include congenital anomalies identified antenatally, or features identified postnatally which are suggestive of an underlying syndrome, known as dysmorphic features. Carrier testing is undertaken when the individual is well, but there is a family history of genetic disease with known reproductive risk. Although carrier status can be

Testing methods

After completing the history and examination, decisions about whether to undertake testing, and which test would be the most suitable can be undertaken. Traditional testing models are driven by a clinical hypothesis. This results in the ability to do a specific, single gene test or a small number of tests on relevant genes. For this traditional targeted testing, pick up rates vary from 0.6% in Fragile X (with a broad phenotype), to 40% for CHARGE (where features are more specific and

Array comparative genomic hybridization (aCGH)

aCGH, or chromosomal microarray (CMA) has replaced traditional karyotyping as the means of detecting chromosome imbalances. Traditional karyotyping involved the direct visualization of chromosomes from peripheral blood lymphocytes, using a microscope, meaning only large alterations – around 5,000,000 base pairs in size – could be easily identified. Diagnostic rates are approximately three times that of karyotyping when aCGH is used (see Table 2). In the neonatal period, aCGH is useful when

Sequencing methods

Next generation sequencing platforms provide the sequencing of millions of small fragments of DNA in parallel, reducing the time taken to sequence the human genome from a decade (as occurred in the Sanger sequencing technology used in the Human Genome Project) to less than a day. Various NGS platforms are available, each using slightly different sequencing techniques, however all allow each of the three million base pairs to be sequenced, or ‘read’ repeatedly, providing depth and accuracy of

Management of ‘off target’ information – incidental findings

Incidental findings are variants of known clinical or reproductive significance, identified during genetic and genomic testing, which are unrelated to the presenting phenotype. The first case in Box 1 demonstrates this: in attempting to establish a diagnosis for intrauterine growth restriction, a cancer predisposition syndrome has been identified. Whilst predictive testing in childhood might be justified in the context of a known family history of VHL to allow biochemical and radiological

Informed consent

How can valid, adequately informed consent be ensured given the volume and complexity of data generated, particularly with respect to incidental findings and variants of unknown significance? It may even be doubted that ‘informed consent’ as it is traditionally defined, is attainable in genomic practice. ‘Generic’ consent involved clinicians and those responsible for consent providing information about broad categories of results – avoiding information overload, yet providing sufficient

Role of epigenetic factors

Epigenetics attempts to summarize the biological processes that connect the genotype of a cell or multicellular organism with the phenotype: the mechanisms or switches capable of turning genes on, off, or altering their expression. In contrast to the genome sequence itself, epigenetic mechanisms are highly susceptible to changes in the environment, such as diet, toxin exposure or behaviour itself.

Three main mechanisms have been identified – DNA methylation, histone modification and the

Summary

As genetic investigations move from the specialist to the general domain, clinicians must be confident in initiating investigations and supporting families to achieve an adequate understanding which allows them to benefit from new genomic technologies. Clinicians and families need a pragmatic understanding that genomic testing may yield clear diagnostic information, it may add nothing, it may identify a change of uncertain significance or it may identify an incidental finding of known clinical

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