Benchmarking outcomes in the Neonatal Intensive Care Unit: Cytogenetic and molecular diagnostic rates in a retrospective cohort

Abstract

Genetic disease and congenital anomalies continue to be a leading cause of neonate mortality and morbidity. A genetic diagnosis in the neonatal intensive care unit (NICU) can be a challenge given the associated genetic heterogeneity and early stage of a disease. We set out to evaluate the outcomes of Medical Genetics consultation in the NICU in terms of cytogenetic and molecular diagnostic rates and impact on management. We retrospectively reviewed 132 charts from patients admitted to the NICU who received a Medical Genetics diagnostic evaluation over a 2 year period. Of the 132 patients reviewed, 26% (34/132) received a cytogenetic or molecular diagnosis based on the Medical Genetics diagnostic evaluation; only 10% (13/132) received a diagnosis during their admission. The additional 16% (21 patients) received their diagnosis following NICU discharge, but based on a genetic test initiated during hospital-stay. Mean time from NICU admission to confirmed diagnosis was 24 days. For those who received a genetic diagnosis, the information was considered beneficial for clinical management in all, and a direct change to medical management occurred for 12% (4/32). For those non-diagnosed infants seen in out-patient follow-up clinic, diagnoses were made in 8% (3/37). The diagnoses made post-discharge from the NICU comprised a greater number of Mendelian disorders and represent an opportunity to improve genetic care. The adoption of diagnostic tools, such as exome sequencing, used in parallel with traditional approaches will improve rate of diagnoses and will have a significant impact, in particular when the differential diagnosis is broad.

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

“…We have shown that while these high-risk neonates embark on their genetic diagnostic odyssey within the first week of life, the turnaround time for most genetic tests, consistent with prior data 13 , 19 , is typically on the order of several weeks to months. The diagnostic odyssey can therefore last for months (or years) owing to the usual stepwise structure of the traditional genetic diagnostic evaluation, where subsequent rounds of testing are sent only after prior testing has been unrevealing.…”

“…Rapid whole genome sequencing in critically-ill newborns and infants has been demonstrated to have a diagnostic yield as high as 50–70% 14 – 17 in a research setting, and a recent retrospective analysis found a diagnostic yield of 36.7% using clinical whole exome sequencing 18 . There is a paucity of information regarding the traditional genetic diagnostic evaluation in the NICU, with one prior study showing a diagnostic yield of 26% for infants who had their initial genetic consultation while in the NICU, though most were diagnosed after NICU discharge 19 . However, NICU infants, particularly non-survivors, could benefit immensely from an expeditious genetic diagnosis.…”

“…However, NICU infants, particularly non-survivors, could benefit immensely from an expeditious genetic diagnosis. It has been shown that finding a genetic diagnosis can aid in the clinical management of critically-ill infants or can lead to the decision to redirect care in the setting of a poor prognosis 16 , 19 , which is of particular importance in the NICU as prior studies have shown that the majority of deaths occur under these circumstances 1 , 3 , 20 . We therefore investigated how many of these NICU infants who died before five years of age had a genetic diagnosis made and analyzed the genetic diagnostic evaluation in this population.…”

The burden of rare diseases

“…With regard to admissions to the NICU, a retrospective review of 132 patients admitted to the NICU over a 2‐year period found that 26% (34/126) were ultimately diagnosed with a genetic condition (Malam et al, ). When considering admissions to a PICU, 5.7% (47/821) corresponded to patients with monogenic or chromosomal disorders, while an additional 4% to patients with congenital anomalies (FitzPatrick, Skeoch, & Tolmie, ).…”

Diagnostic clarity of exome sequencing following negative comprehensive panel testing in the neonatal intensive care unit

“…Rare disease contributes significantly to the mortality and morbidity of newborns admitted to the neonatal intensive care unit (NICU) (Berger & Hofer, ; MacDorman, Mathews, & Centers for Disease Control and Prevention (CDC), 2013). These typically complex conditions often have an underlying chromosomal or single gene cause; however, most newborns will not receive a timely genetic diagnosis during their hospital admission and early life (Malam et al, ). This represents a missed opportunity as these infants may not receive the medical or surgical management to maximize outcomes, or have appropriate surveillance plans initiated to minimize the later burden of disease.…”