Articles
Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings

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Summary

Background

Genetic disorders and congenital anomalies are the leading causes of infant mortality. Diagnosis of most genetic diseases in neonatal and paediatric intensive care units (NICU and PICU) is not sufficiently timely to guide acute clinical management. We used rapid whole-genome sequencing (STATseq) in a level 4 NICU and PICU to assess the rate and types of molecular diagnoses, and the prevalence, types, and effect of diagnoses that are likely to change medical management in critically ill infants.

Methods

We did a retrospective comparison of STATseq and standard genetic testing in a case series from the NICU and PICU of a large children's hospital between Nov 11, 2011, and Oct 1, 2014. The participants were families with an infant younger than 4 months with an acute illness of suspected genetic cause. The intervention was STATseq of trios (both parents and their affected infant). The main measures were the diagnostic rate, time to diagnosis, and rate of change in management after standard genetic testing and STATseq.

Findings

20 (57%) of 35 infants were diagnosed with a genetic disease by use of STATseq and three (9%) of 32 by use of standard genetic testing (p=0·0002). Median time to genome analysis was 5 days (range 3–153) and median time to STATseq report was 23 days (5–912). 13 (65%) of 20 STATseq diagnoses were associated with de-novo mutations. Acute clinical usefulness was noted in 13 (65%) of 20 infants with a STATseq diagnosis, four (20%) had diagnoses with strongly favourable effects on management, and six (30%) were started on palliative care. 120-day mortality was 57% (12 of 21) in infants with a genetic diagnosis.

Interpretation

In selected acutely ill infants, STATseq had a high rate of diagnosis of genetic disorders. Most diagnoses altered the management of infants in the NICU or PICU. The very high infant mortality rate indicates a substantial need for rapid genomic diagnoses to be allied with a novel framework for precision medicine for infants in NICU and PICU who are diagnosed with genetic diseases to improve outcomes.

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, and National Center for Advancing Translational Sciences.

Introduction

Since the progression of genetic diseases can be rapid in infants, diagnosis must be swift to permit timely consideration of interventions that lessen morbidity and mortality rates.1, 2, 3, 4, 5, 6, 7 There are more than 4300 genetic diseases of known causes. Collectively, they are the leading causes of infant mortality, particularly in neonatal intensive care units (NICUs),4 and in paediatric intensive care units (PICUs).8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 The premise of genomic or precision medicine is that genetic diagnosis might allow supplementation of empirical, phenotype-driven management with genotype-differentiated treatment and genetic counselling.19, 20, 21, 22, 23, 24, 25, 26 Timely molecular diagnoses of suspected genetic disorders had been largely precluded in acutely ill infants because of substantial clinical and genetic heterogeneity and tardiness of getting results from standard genetic tests, such as gene sequencing.5, 19, 20, 23, 24, 27, 28, 29, 30, 31, 32 Although appropriate NICU treatment is one of the most cost-effective methods of high-cost health care, patients' long-term outcomes are diverse.1, 8, 33, 34 In genetic diseases with poor prognosis, rapid diagnosis might enable early discussions with parents about palliative care to minimise suffering.8, 34

We previously reported methods for diagnosing genetic disorders with rapid whole-genome sequencing (STATseq) in 50 h.5 This method was used to simultaneously test almost all Mendelian illnesses and was postulated to give a diagnosis in time to guide clinical management of acutely ill infants and children in the NICU or PICU.5 In our study, we report the rate and types of genetic diagnoses with STATseq and standard genetic tests in the first 35 infants in a regional (level 4) NICU and PICU at a quaternary children's hospital and the prevalence, types, and results of medical findings.

Research in context

Evidence before this study

We searched PubMed with the terms “diagnosis”, “infant”, and “genome sequencing” or “exome sequencing”. There were no date or language restrictions. We found several case reports and five retrospective clinical series related to the usefulness of genomic sequencing for molecular diagnosis in infants in whom the differential diagnosis included monogenic diseases. The exome is the 1·5% of the genome that encodes proteins, and exome sequencing has until now been favoured over genome sequencing because of costs. The evidence before this study was that whole-genome or exome sequencing results in a molecular diagnosis in 25–73% of children with possible monogenic diseases. No prospective studies of the usefulness of genome or exome sequencing for diagnosis of monogenic diseases have yet been published. The usefulness of genome or exome sequencing for molecular diagnosis in neonatal and paediatric intensive care units (NICUs or PICUs), where genetic diseases are the leading cause of death and daily costs of care are commensurate with those of whole-genome sequencing, have not been investigated. The temporal dynamics of monogenic disease progression in the NICU or PICU, or the implications for calibration of time-to-diagnosis and time-to-intervention have not been investigated.

Added value of this study

We report that 57% of 35 infants were diagnosed with monogenic disease in NICU or PICU with rapid whole-genome sequencing (STATseq). Our study is the first of clinical usefulness of genomic diagnoses in acute illnesses in infants in NICU or PICU. In agreement with the results of two previous reports of the clinical effect of genomic diagnoses in children with non-acute neurodevelopmental disabilities, we noted that 65% of STATseq diagnoses had immediate clinical usefulness, including a strongly favourable effect on management in 20% and institution of palliative care in 30% of infants.

Implications of all the available evidence

The clinical implication of the available evidence is that clinicians should consider genome or exome sequencing for diagnosis in NICU or PICU for infants in whom the differential diagnosis includes monogenic diseases. However, further studies are needed to identify the characteristics of infants in whom the likelihood of a diagnosis is sufficiently likely to warrant the cost of genome sequencing, and how rapid molecular diagnoses can be integrated into clinical workflows to improve outcomes in newborns with acute genetic diseases.

Section snippets

Study design and patients

This study was undertaken at Children's Mercy–Kansas City, MO, USA. It was a retrospective comparison of the diagnostic rate, time to diagnosis, and types of molecular diagnoses of standard clinical genetic testing (reference test), as clinically indicated, with STATseq (index test) in a case series. Participants were parent–child trios, enrolled in a research biorepository who had genomic sequencing and standard diagnostic tests to diagnose monogenic disorders of unknown cause in the affected

Results

49 families with infants or children who were acutely ill or had died were enrolled and had rapid whole-genome sequencing (STATseq) of parent–child trios. 35 of these families met the inclusion criteria for this study (figure 2). The phenotypes for which infants had been nominated to have STATseq were diverse and were typically present at birth (table 1). The most common phenotypes were congenital (26%) and neurological anomalies (20%; table 1). However, infants usually had complex clinical

Discussion

Rapid, clinical genome sequencing (STATseq) was feasible in a NICU or PICU and provided genetic diagnoses for most of the enrolled infants with a wide range of clinical presentations. Since genetic diseases are the leading cause of death in the NICU and PICU, and overall infant mortality,2, 4, 5, 8, 9, 10, 11, 13, 15, 16, 21, 26, 33, 34 these results might have broad implications for the NICU or PICU practice.

57% of the cases had a definitive diagnosis with STATseq, significantly higher than

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