Peri-mortem evaluation of infants who die without a diagnosis: focus on advances in genomic technology

Abstract

Infants who die within the first weeks to months of life may have genetic disorders, though many die without a confirmed diagnosis. Non-genetic conditions may also be responsible for unexplained infant deaths, and the diagnosis may be reliant upon studies performed in the peri-mortem period. Neonatologists, obstetricians, or pediatricians caring for these children and their families may be unsure of which investigations can and should be performed in the setting of a newborn or infant who is dying or has died. Recent advances in genomic sequencing technology may provide additional diagnostic options, though the interpretation of genetic variants discovered by this technique may be contingent upon clinical phenotype information that is obtained peri-mortem or upon autopsy. We have reviewed the current literature concerning the evaluation of an unexplained neonatal or infantile demise and synthesized a diagnostic approach, with a focus on the contribution of new and emerging genomic technologies.

Figure 1.. Algorithm for unexpected and unexplained neonatal death.

This algorithm provides a comprehensive list of testing options; actual testing should be individualized to the neonate’s circumstance. The physician should use his or her judgment as to which investigatory approaches should be taken to ensure optimal diagnostic yield with the least amount of intervention.

Figure 2.. Molecular autopsy for unexplained neonatal death.

Guidelines for obtaining samples for genetic evaluation. Tissue biopsies from affected organs can also be obtained prior to death. Pre- or post-mortem biopsied tissue to be saved for genetic testing should be frozen immediately, not formalin-fixed or paraffin-embedded. See Table 2 for further details on collection and storage.