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.