Genetic disorders and mortality in infancy and early childhood: delayed diagnoses and missed opportunities

Abstract

Purpose: Infants admitted to a level IV neonatal intensive care unit (NICU) who do not survive early childhood are a population that is probably enriched for rare genetic disease; we therefore characterized their genetic diagnostic evaluation.

Methods: This is a retrospective analysis of infants admitted to our NICU between 1 January 2011 and 31 December 2015 who were deceased at the time of records review, with age at death less than 5 years.

Results: A total of 2,670 infants were admitted; 170 later died. One hundred six of 170 (62%) had an evaluation for a genetic or metabolic disorder. Forty-seven of 170 (28%) had laboratory-confirmed genetic diagnoses, although 14/47 (30%) diagnoses were made postmortem. Infants evaluated for a genetic disorder spent more time in the NICU (median 13.5 vs. 5.0 days; p = 0.003), were older at death (median 92.0 vs. 17.5 days; p < 0.001), and had similarly high rates of redirection of care (86% vs. 79%; p = 0.28).

Conclusion: Genetic disorders were suspected in many infants but found in a minority. Approximately one-third of diagnosed infants died before a laboratory-confirmed genetic diagnosis was made. This highlights the need to improve genetic diagnostic evaluation in the NICU, particularly to support end-of-life decision making.

Keywords: diagnostic odyssey; genetic diagnosis; infancy; mortality; neonatal intensive care unit.

Figure 1. The genetic or metabolic evaluation and causes of death

“Other” includes four infants who died during or from complications of a medical procedure.

Figure 2. Timing of the molecular genetic diagnosis

*Two postnatal (birth – 6 months), one postnatal (6 months – 2 years) and two postmortem diagnoses involve two variants thought to cause an autosomal recessive disorder without confirmation of phase documented in the medical record. Two of these diagnoses (one postnatal and one postmortem) also involve a VUS found in combination with a likely pathogenic or pathogenic variant.