Genomics in action

Screening midwives are involved in the application, training and monitoring of the screening standards within the trust. They work to ensure parents and clinicians understand the implications of screening, and identify parents who are at a higher chance of conditions being screened for. They then ensure that the parent is on the correct care pathway within an appropriate timeframe.

Fetal medicine midwives support expectant parents after a diagnosis of a fetal anomaly found on ultrasound examination. This support includes provision of information about the fetal anomaly, as well as pre-test counselling for those who choose to have a diagnostic test (for example, CVS or amniocentesis). They also support expectant parents to make difficult reproductive decisions and signpost them for additional advice and counselling.

Consultant midwives have a broad remit, though some specialise in a specific area such as public health. As well as clinical practice, they have a leadership, education and practice development and research role.  They support midwives to practise effectively and are well placed to integrate genomics within their areas of responsibility.

Midwives work in partnership with obstetricians, physicians and specialist nurses to provide holistic care for a range of specific diseases within a ‘joint’ complex or high-risk clinic.  Here, they see expectant parents affected by a pre-existing medical condition, for example, diabetes, epilepsy or high blood pressure – all of which could have an impact on the expectant parent and baby during pregnancy. Some of these conditions may have a genetic basis that will require a genomic evaluation.

Some midwives trained in ultrasound routinely carry out an examination of the developing fetus to exclude structural anomalies as well as to obtain specific measurements to evaluate its growth, it is also important that midwife sonographers have an understanding of genomics, as ultrasound will inform the phenotype in some genomic conditions, for example, skeletal anomalies.

Expectant parents affected by a medical or genetic condition are already considered to be ‘high-risk’ before they reach the delivery suite. As such, midwife advance practitioners need to have an understanding of genomics, given the risks associated with labour and delivery. Having awareness about genetic conditions can mitigate issues during the intrapartum period. For example, knowing that an expectant parent who has Elhers-Danlos syndrome may have a poor response to lignocaine and experience a significant drop in blood pressure, and may be more prone to a precipitate active labour.

Research midwives play an important role in genomic research studies related to pregnancy. A number of these are already underway, with many more arising in future from the Genomic Medicine Service Alliances (GMSAs) and the local Genomics England Clinical Interpretation Partnership (GeCIP).

NIPT works by analysing the small fragments of DNA – known as cell free DNA (cfDNA) – floating in the expectant parent’s blood. Most of these fragments will be from the parent, but a proportion will come from the placenta and therefore carry the DNA of the fetus.

The test is primarily used to detect aneuploidies – where an non-standard number of chromosomes is present in each cell – specifically trisomies, such as Down, Edwards and Patau syndromes.

As fetal sex is determined by chromosomes, accurate sex determination is also possible from a gestation of around nine weeks. Identifying sex determination at an earlier gestation can assist parents with x-linked conditions to make decisions on the pregnancy pathway.

NIPT is being introduced into the NHS as an evaluative roll out from 1 June 2021, so it’s important to learn more about its benefits, limitations and availability. You can find guidance for NIPT on the gov.uk webpage.

RP-WES is a perinatal test that is supported by pre-test counselling (through fetal medicine and clinical genetics departments) and sample analysis (through genomics laboratory hubs).

Unlike whole genome sequencing which looks at a person’s entire genome, RP-WES looks for a limited number of fetal anomalies by reading all the DNA letters within the 1-2% of the genome that codes for proteins (the exome). It looks more accurately for known genomic variants in consented ‘trios’ (parental and fetal samples) that are unexplained by chromosomal karyotype and microarray.

After interpretation by clinical scientists, the results from RP-WES can provide benefits that would not otherwise be possible. For example, research has shown that, with expert multidisciplinary review for case selection and data interpretation, RP-WES yields timely, high diagnostic rates of around 80% in fetuses presenting with unexpected skeletal anomalies.

You can find out more about RP-WES, including eligibility and exclusion criteria, clinical examples and testing pathways, in the NHS guidance document: ‘Rapid Exome Sequencing Service for fetal anomalies testing’.

This is a type of test that can indicate whether or not the parent has a haemoglobinopathy or that they are a carrier. Subsequent genomic testing can be done to determine the specific DNA variant.

Antenatal screening should be carried out according to the guidelines of the NHS Sickle Cell and Thalassaemia Screening Programme, with the aim to identify when a pregnancy may have an increased risk of a haemoglobin disorder. Newborn screening and, when necessary, follow-up testing and referral, should also be carried out under these guidelines.

This test is used in cases where a structural anomaly is suspected in the genome. For example, it could be offered a parent with a history of multiple pregnancy losses or infertility, which could be due to a balanced chromosome rearrangement.

The test works by treating chromosomes so that they can be viewed under a microscope, enabling any large duplications, deletions and translocations to be seen and diagnosed.

If ultrasound scans suggest the presence of a chromosomal anomaly, and the result of a qf-PCR test is normal, microarray tests can determine if the fetus has too much (a duplication) or too little (a deletion) chromosomal material.

Microarrays are also used neonatally, for example in children that have developmental delay or other health problems that could have an underlying genetic basis.

A blood spot test is carried out as part of the newborn blood spot (NBS) screening programme when the baby is five days old. The test screens for nine rare and serious health conditions.

The blood spots are used to carry out a series of biochemical tests that screen for specific conditions by looking for metabolic markers. If a test is abnormal, it may then be appropriate to initiate further genomic testing to confirm the diagnosis or identify the genetic variant responsible for that condition.

More information about the newborn blood spot test is available here, in the neonatal care section of this resource.

This test measures the amount of DNA associated with chromosomes linked to aneuploidy conditions, such as Down syndrome, Edwards syndrome and Patau syndrome. It works by amplifying small sections of DNA and then labelling them with fluorescent tags.

The test is typically done when there is a suspicion of an aneuploidy syndrome because of combined or quadruple test results, abnormalities detected on an ultrasound scan, a previous aneuploid pregnancy, or when the parent has an increased risk of a specific aneuploidy syndrome.

Targeted variant testing is where a small part of the genome is sequenced to look for the specific variant or variants known to cause a particular condition. This includes cystic fibrosis, where testing may be requested when one or both parents are carriers or have a family history of the condition, or when fetal echogenic bowel is seen on ultrasound.

It is typically carried on fetal DNA samples obtained from CVS or amniocentesis.

Typically, this test is arranged via clinical genetics services following genetic counselling.

After finding out that she was pregnant with her second child, Holly informed her GP who referred her to a local community midwife, Ruth.

Ruth contacted Holly to arrange the booking appointment, which she explained takes around an hour and provides the chance to take a medical and family history to allow the correct pregnancy pathway to be taken.

During the appointment, Ruth asked Holly a number of questions, including whether there is a known family history of any medical conditions, or if she or any primary relatives has ever had any genetic counselling.

Holly said that she and her father have asthma but there are no other conditions that she knows about that run in the family. She also said that she wasn’t aware of any family members who had had genetic counselling.

Ruth, knowing how important family history could be for adapting care, asked Holly to let her or any healthcare professional know if she thought of anything or received any new information at any stage of the pregnancy.

Note: If Holly had indicated to Ruth that she had a family history of MCADD, then she would have been referred to a paediatric specialist metabolic team. Additionally, if her other child, Jenny, had previously been diagnosed with MCADD, then this referral would also have been made.

At 28 weeks, Ruth visited Holly at home to carry out an antenatal assessment and to take blood to check for anaemia and antibody levels. Before leaving, Ruth gave Holly a few booklets which described specific checks that would be carried out on her baby after the birth. One of the booklets referred to the ‘newborn blood spot screening programme’, a test that Holly remembered from her first pregnancy.

Holly told Ruth that her first child received a normal result after the blood spot test, which she described as painful and difficult to watch. Ruth empathised with her and made the benefits of the test clear. Ruth told Holly that, each year, a small number of babies get a positive result from the test, and in these cases, early diagnosis and prompt treatment can help to avoid severe developmental delay or other serious health problems. She mentioned that, sometimes, a special diet would be all that was needed to save the baby’s life. Holly took the booklet.

Jack was delivered at 39 weeks on the midwifery-led unit. Pete, Holly’s partner, was there for the birth. The birth went smoothly with no notable complications or problems. A few hours later, both Holly and Jack were perfectly healthy with breastfeeding going well, and so Ruth discharged them.

Ruth visited Holly the next day for the primary visit: a neonatal check including the opportunity for Jack to have the blood spot test. Ruth informed Holly and Pete about the importance of the test, emphasising that a positive result, although rare, was a possibility, and finding out early could help to provide effective and potentially life-saving treatment for Jack. She also spoke about the limitations of the test, and told the parents that screening is not perfect, and a baby who is negative could go on to have a condition.

After listening to Ruth and remembering the booklet Holly had been given during her antenatal assessment, the family agreed to go ahead and get Jack tested that day. Ruth then obtained blood from Jack’s heel for the test. She informed the couple that after Jack’s sample had been screened, all remaining residual blood spots would be kept by the laboratory for research studies. Ruth recorded the details of the neonatal examination, consent consultation, procedure and discussion in Jack’s neonatal notes.

Before leaving, Ruth told Holly and Pete that she would contact them if there were any problems. Otherwise, the couple would be notified in six to eight weeks by letter or from a healthcare professional.

Two days later, Ruth received a phone call from the metabolic screening laboratory who informed her that Jack had tested positive for a rare and life-threatening metabolic disorder called medium-chain acyl-CoA dehydrogenase deficiency (MCADD). Ruth called Holly and Pete immediately to tell them that Jack had tested positive for a condition, and that she needed to see them to explain what the laboratory found.

Ruth met Holly and Pete to explain the condition, what causes it and how it was detected by the blood spot test in a clear and uncomplicated way. She made sure to answer any questions and took a note to find out anything she couldn’t answer.

Ruth asked how Jack had been since she last saw him. The family agreed that he wasn’t feeding well and was drowsy. Ruth recognised these as red flags and contacted the paediatric metabolic team immediately to arrange a consultation for Jack.

Note: Metabolic crises can escalate very quickly in people with MCADD, especially if a person develops a high temperature, vomiting or diarrhoea because the body requires more energy to combat the symptoms.

In the meantime, Ruth advised Holly to feed Jack every couple of hours and observe him for excessive sleeping and rapid breathing. Ruth gave the couple a leaflet to read with more information about MCADD.

Pete asked why Jack was affected by MCADD but not the rest of the family. Ruth explained the autosomal recessive pattern of inheritance, drawing a simple diagram while talking through it. She explained that everyone has a pair of genes that make the medium chain acyl-CoA dehydrogenase enzyme, and that neither of Jack’s pair of genes worked correctly because he inherited one non-working gene from Holly and another non-working gene from Pete.

She went on to explain that Holly and Pete are both carriers, each with one healthy copy of the gene, and this is why they don’t have MCADD themselves. She explained that when both parents are carriers, there is a 1-in-4 chance of having a child affected by MCADD, like Jack; a 1-in-4 chance of having an unaffected child, like Jenny; and a 2-in-4 chance of having a child who is a carrier.

Ruth also mentioned that any future pregnancies would be managed differently now that there is a known family history of MCADD, with immediate referral to the paediatric specialist metabolic team.