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Globally, there are more than 7,000 known rare diseases, of which 80 per cent have an underlying genetic aetiology¹. Although individually rare, affecting fewer than one in 2,000 individuals, birth defects – a subset of rare diseases – are reported in approximately 2.4 per cent of live births in Singapore².

In addition, about 50 per cent of rare diseases present in childhood, and up to one in three children admitted to the paediatric intensive care unit (ICU) is suspected to have an underlying genetic disease³.

The diagnostic odyssey for most patients with rare diseases can be lengthy, and often include multiple evaluations by different healthcare providers, without a definitive diagnosis.

On average, it is estimated that a patient with a rare disease will see up to eight different specialists, and wait about 7.6 years to achieve a diagnosis. About 30 per cent of children with rare diseases die by the age of five years, some without ever receiving a correct diagnosis.

In recent years, the increasing application of clinical exome sequencing in the paediatric ICU setting has been gaining traction, where a short turnaround time (usually within two weeks) coupled with a relatively high diagnostic yield (30% to 40%) allows for significant changes in the medical management of patients with rare diseases^{4, 5}, and, at the same time, provides patients and their families an opportunity to get answers.

A genetic diagnosis in 40 per cent of RapidSeq cases

RapidSeq (Rapid Genomic Sequencing test) was launched at KK Women's and Children's Hospital (KKH) in April 2018, with the aim to provide a genetic diagnosis within two weeks for critically-ill patients in the Neonatal Intensive Care Unit (NICU) and Children's Intensive Care Unit (CICU) who are suspected to have a genetic disorder. In comparison, a waiting period of three months is usual using traditional methods of genetic testing.

From April 2018 to January 2019, 10 cases were enrolled into RapidSeq, with the youngest patient being just three days old. Seven were patients from NICU, two were patients from CICU, and one was a stored fetal DNA sample.

In four of the 10 cases (40%) a genetic diagnosis was achieved. For three of these, the diagnosis led to changes being implemented in the patient's clinical management plan. The median turnaround time for results was nine working days, with six days being the shortest, and 12 days the longest.

We highlight two cases where the RapidSeq diagnosis directly impacted the management of the patient, and aided counselling for the family.

Case 1: MIRAGE syndrome

Patient A was born premature and presented with hyperpigmentation of the skin. She was later found to have congenital adrenal insufficiency, with hypoplastic adrenal gland as well as severe persistent thrombocytopenia (low platelet count).

Enrolled in RapidSeq, the patient was found to have a de novo known pathogenic mutation C>G in the SAMD9 gene (indicated by the red box in Figure 1). Mutations in the SAMD9 gene are associated with MIRAGE (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital phenotypes and Enteropathy) syndrome, which is consistent with the patient's clinical presentation. This disorder was first discovered in 2016⁶ and there are fewer than 30 known cases worldwide.

This unifying diagnosis provided more clarity to the patient's care team, and surveillance was instituted to observe for associated complications such as haematological malignancy and immunodeficiency. The diagnosis also ended the diagnostic odyssey for the patient and family, providing clarity – through genetic counselling – on the condition and her expected developmental prognosis. The patient is currently doing well and receiving follow up care at KKH.

Case 2: Cranioectodermal dysplasia

Patient B presented for prenatal genetic counselling while pregnant. She had had a previous pregnancy which had been terminated as the fetus showed signs of skeletal dysplasia. No genetic diagnosis was made at that time, but the couple had been counselled that the risk of recurrence in subsequent pregnancies was low. However, an antenatal scan in the second pregnancy showed fetal anomalies similar to the first pregnancy.

Using a stored fetal DNA sample from the first pregnancy, the family was enrolled in RapidSeq. The team discovered pathogenic variants detected in IFT122 gene, which is consistent with the diagnosis of cranioectodermal dysplasia.

Cranioectodermal dysplasia is a multisystemic disorder causing skeletal dysplasia, ectodermal defects and joint laxity. Fewer than 60 cases have been reported in literature⁷.

Based on these results, the patient underwent amniocentesis to obtain a definitive diagnosis – which confirmed the same pathogenic variants in the IFT122 gene. As the condition is inherited recessively, the risk of recurrence is 25 per cent, and the couple was counselled accordingly and provided options regarding future pregnancies.

High diagnostic yield with a short turnaround time

The first of its kind in the local setting, RapidSeq is made possible through a collaborative effort between the Genetics Service, DNA Diagnostic and Research laboratory and Translational laboratory, with specialists from NICU and CICU.

Eligible patients are first assessed by the clinical geneticist, and enrolled patients undergo sequencing targeting exonic regions of 4,800 genes associated with human diseases (also referred to as the clinical exome). The variants generated are filtered and prioritised using in-house computational algorithms.

Shortlisted variants are then correlated with clinical phenotype and classified based on established guidelines. Lastly, a clinical report is generated, which is shared with the primary care team – to inform the management of the patient's condition – as well as the patient's family, to provide answers and a measure of closure.

A positive genetic diagnosis in critically-ill patients can play a valuable role in guiding clinical care management and therapeutics. This can result in benefits such as treatment modification, initiating a new treatment, or surfacing the need to involve other specialists in the clinical care of the child.

It can also guide the care team in potentially reducing unnecessary investigations such as stopping a treatment that is not useful, or precluding a potentially invasive measure.

In some cases, a diagnosis with a dire prognosis can help to bring closure, and enable the care team and family to discuss treatment limitations and palliative care options. Additionally, the family will benefit from genetic counselling about the risk of recurrence in future pregnancies, for the same genetic disorder.

Where a patient's condition remains undiagnosed, other forms of tests, including whole genome sequencing, can be offered as per their clinical indication, to better understand their conditions.

Research efforts are ongoing at KKH to ascertain the diagnosis by using newer tools as they become available. Regardless, the patient will continue to be managed symptomatically albeit without a diagnosis.

Regardless of the diagnosis, RapidSeq enables the critically-ill patient and their family to receive information and, in some cases answers, in a timely manner. This is in comparison to a longer wait time for serial genetic testing in a stepwise manner with more traditional technologies.

With the promising results of these first 10 patients, the team continues to explore the impact and benefits of RapidSeq on optimising clinical care for paediatric patients in the ICU.

​Dr Ting Teck Wah, Consultant, Genetics Service, KK Women’s and Children’s Hospital Dr Ting Teck Wah graduated from the National University of Singapore in 2006 and completed his paediatric medicine specialist training in 2014. His research interests are in the area of inborn errors of metabolism and genetics of neurodevelopmental delay. In 2017, Dr Ting completed his fellowship in the metabolic department of The Royal Children’s Hospital Melbourne, Australia.

​Dr Saumya Jamuar, Senior Consultant, Genetics Service, KK Women’s and Children’s Hospital Trained in clinical genetics at the Harvard Medical School in Boston, United States, Dr Saumya Jamuar is a clinical geneticist at KKH, and serves as the lead primary investigator of the Singapore Childhood Undiagnosed Disease Programme. Dr Jamuar is also the clinical director of the SingHealth Duke-NUS Institute of Precision Medicine. Actively involved in translational research, Dr Jamuar has published in top tier journals and has won multiple awards for his research, including the SingHealth Outstanding Young Researcher Award in 2015.