A New Method for Neonatal and Prenatal Diagnosis

There are over half a billion people living with rare diseases - one in every 17 people , or 7% of the world’s population. It feels counter-intuitive, half a billion of anything being rare, but there are more than 7,000 rare diseases classified worldwide, 80% of them with a genetic basis that can be attributed to changes (mutations) in one or more genes.

Rare diseases can manifest in adulthood, but the majority of them present in childhood, particularly in newborns. Twenty percent of infant deaths are a result of such conditions, so the work performed in Neonatal Intensive Care Units (NICUs) and Pediatric Intensive Care Units (PICUs) is some of the most urgent and vital that takes place.

The NICU is a specialized care environment for premature babies or those presenting symptoms. Here they have access to cutting edge diagnostic tools; from MRI and CAT scans to whole genome sequencing, which is used in the rarest and most severe cases, where time is of the essence or no other diagnostic methods are possible. The PICU offers a similar care environment to children over 6 months of age and also offers complex operations and post-operative care.

In many of these cases the genetic variant responsible is so rare and undocumented that doctors might be seeing it for the very first time. These disorders can be difficult to diagnose, as they have many symptoms that are shared by other conditions. These may be phenocopies, in which patients manifest the same clinical symptoms but the underlying genetic causes are different, or they may simply be unique cases in which doctors or clinicians are faced with a variant that has never been seen or documented before. Take, for example, cases of epilepsy caused by different mutations in the SCN1A gene, in which the phenotypes and seizures on the surface appear identical, but can have drastically diverse consequences for prognosis, medication and future pregnancies.

With traditional methods, this could set the child on a diagnostic odyssey of many years as each suspected condition was methodically eliminated, but with clinical genomics, answers can be received, and treatment delivered, in a matter of days.

Clinical genomics is the act of taking an individual’s entire DNA code, all 3.2 billion letters of it, sequencing it (converting it into electronic data) and comparing it to a human reference genome, in order to identify variants and mutations that may be causing a disease or condition. This sequence data is a huge amount of information for doctors and clinicians to work through, and this is where interpretation software platforms such as SapientiaTM, from Cambridge based Congenica, are proving invaluable.

Sapientia takes this sequence and displays it to the doctors and clinicians in an intuitive graphical browser. Here, the whole sequence, or specific genes, can be examined and the potential effects of any variants scrutinised. By placing a huge amount of computing power at the doctors’ and clinicians’ backs and a vast array of medical insight at their fingertips, Sapientia empowers them to make actionable, clinically relevant decisions quickly and confidently.

With a diagnosis the family will have realistic prognostic expectations, clear information on reproductive options and definite focus for management of the condition. In cases where treatment is possible, the more timely the intervention, the more likely it will be that doctors will be able to alleviate symptoms, halt further damage to the child’s health or at the very least direct care towards palliative options.

Bringing the Right People to the Right Information

All parents are offered a screening test on the birth of their child, using a drop of blood taken from the newborn’s heel moments after birth. For some conditions, doctors know that an early intervention can drastically change potential prognosis for the newborn, and in these cases the blood sample will be used for whole genome sequencing (WGS). This sample is then sequenced, processed and introduced into Sapientia. Sapientia enables easy viewing the child’s individual genomic data, including the genes, phenotypes and pedigrees, as well as those of their parents or other family members who have submitted samples.

The presented data is then carefully examined by registered Clinical Scientists who identify variants and assign pathogenicity (their likelihood to cause or affect a known disease or disorder) using the worldwide standardised Human Phenotype Ontology (HPO) terms. These assignments are backed up by expert annotation and supported by literature from the world’s leading academic journals and periodicals.

This information is then displayed graphically in a genome browser for members of the healthcare team. The system then enables leading specialists from around the world to consult on the case. This enormously expands the catchment of experts who are able to share their findings and results, making it easy for the multi-disciplinary teams to add or review annotations, cross reference findings, view pedigrees and trios and form the most effective actionable clinical reports.

Multi-disciplinary teams such as these are integral to synergistic healthcare. In addition to the expected doctors and specialists, you also find physiotherapists, psychologists, dieticians and even play specialists.

Then there are the parents themselves who have a crucial part to play in the form of caregivers. Even if the child is sedated, parental contact is incredibly important; the familiar heartbeat of a mother, skin to skin contact, the recognisable tones of voice or innate scent of their skin are all proven to aid bonding and reduce stress in the child.

A matter of time

In NICU or PICU the child’s condition can deteriorate very quickly. In many cases the illness could have already progressed under the surface and only recently started showing symptoms, meaning the risks from the condition may already have matured and become more dangerous.

The application of genomics into clinical practice allows faster and more accurate diagnoses leading to the most targeted and effective medical treatments to be applied, management steps to be taken, and irreversible neurological and developmental problems potentially averted.

Using traditional medical methods, investigative testing and systematic elimination of potential diseases, the average diagnostic odyssey faced by any patient, adult or child, consists of an average of 7.3 clinicians taking 4.8 years of tests to deliver an actionable, clinical diagnosis. It is a tragic truth that the multitude of these children will not see their fifth birthday. Sapientia has the power to greatly curtail that diagnostic odyssey to an average of only one clinician and just five days. The impact is unequivocal.

Sapientia is helping to save the most vulnerable of lives by providing clinically actionable information, which can be carried out within the critically tight window available to these doctors and clinicians on the NICU and PICU wards.

Congenica was founded, and Sapientia developed, with the aim of integrating genomics into healthcare in a way that would provide tangible benefits where patients need them most. Genomics is giving doctors the greatest insight into the patient that they have ever had. It may not be perfect quite yet, but the future may see a form of medical ability unlike anything previously seen outside of science fiction.