Characterization of 297 NICU Patients with Congenital Anomalies Evaluated with Genome Sequencing
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction:
Congenital anomalies remain a common indication for Neonatal Intensive Care Unit (NICU) admission. It is well-established that many congenital anomalies are caused by underlying genetic disease. However, there are limited studies describing the types of congenital anomalies in a NICU cohort or diagnostic variants identified following genomic testing. In this prospective cohort study, we describe the types of congenital anomalies, diagnostic yield, diagnostic variants, and hospital outcomes of NICU patients who underwent genome sequencing (GS).
Methods:
This cohort included 297 patients admitted to three NICUs at Riley Children’s Hospital, in Indianapolis, Indiana from May 2022 to November 2023. Patients received GS from Baylor Laboratories due to the presence of at least one congenital anomaly identified through manual chart review. Prior to testing, each patient had a list of Human Phenotype Ontology (HPO) terms created. Each patient’s Human Phenotype Ontology (HPO) terms were then mapped to body systems and validated by an internal software (‘Phenobert’). The body systems of interest included musculoskeletal, nervous, genitourinary, digestive, cardiovascular, head/neck/eye/ear, pulmonary, or other. Patients with anomalies in multiple body systems constituted the “More than One System” category. Patients with anomalies isolated to one body system constituted the “Isolated System” category.
From positive genetic diagnoses, diagnostic variants were described by genotype characteristics: Single Nucleotide Variants (SNVs) or Copy Number Variants (CNVs). CNVs were organized as microduplications, microdeletions, or aneuploidies. SNVs were classified as intronic or exonic and further as substitutions, insertions, deletions, or indels, with biological roles analyzed via Panther. Length of stay (LOS) was the primary hospital outcome studied.
Chi-squared, Fisher’s exact, Mantel-Haenszel, and Wilcoxon tests were used to assess statistical differences in the genetic diagnosis rates and LOS among comparison groups.
Results:
The majority of the cohort had anomalies in multiple systems compared to a single system (59% vs. 41%), with a higher genetic diagnosis rate in the "More Than One System" group compared to the “Isolated System” group (32% vs. 21.3%, p=0.04). Of the cohort, 71.4% had anomalies in cardiac, 12.8% in digestive, 29.0% in genitourinary, 29.3% in head/neck/eye/ear, 20.9% in musculoskeletal, 13.8% in nervous, 10.8% in pulmonary, and 5.4% in other. Among the 82 diagnosed patients, 38 CNVs (60.5% microdeletions) and 47 SNVs (87.2% exonic, 63.8% substitutions) were identified. Panther analysis of 41 unique SNV genes showed the top three biological processes were cellular processes, biological regulation, and developmental processes (63.4%).
In the “Isolated System” group, patients with a genetic diagnosis had a longer LOS (median 94 vs. 16 days, p = 0.005). In the “More Than One System” group, the presence or absence of a genetic diagnosis did not affect LOS (median 30.5 vs. 35 days, p > 0.05).
Conclusion:
NICU patients present with a wide range of congenital anomalies across organ systems. While anomalies in multiple organ systems predicted a greater chance of a genetic diagnosis after GS, a significant number of patients with anomalies in one organ system received a genetic diagnosis, highlighting the utility of GS in this population. Genes linked to congenital anomalies in a NICU cohort are often involved in ubiquitous cellular functions expressed across multiple organ systems and cause early symptomatic disease when carrying pathologic variants. While most patients had SNVs, a significant minority had CNVs, highlighting the superiority of GS to detect a variety of genetic mechanisms which result in congenital anomalies.
Patients with congenital anomalies had LOSs extending beyond the neonatal period, with patients having an isolated system anomaly and a genetic diagnosis experiencing the longest hospitalizations. Further study is needed to understand the detectable rate of genetic disease in patients with congenital anomalies and how a genetic diagnosis impacts the NICU stay.
Congenital anomalies remain a common indication for Neonatal Intensive Care Unit (NICU) admission. It is well-established that many congenital anomalies are caused by underlying genetic disease. However, there are limited studies describing the types of congenital anomalies in a NICU cohort or diagnostic variants identified following genomic testing. In this prospective cohort study, we describe the types of congenital anomalies, diagnostic yield, diagnostic variants, and hospital outcomes of NICU patients who underwent genome sequencing (GS).
Methods:
This cohort included 297 patients admitted to three NICUs at Riley Children’s Hospital, in Indianapolis, Indiana from May 2022 to November 2023. Patients received GS from Baylor Laboratories due to the presence of at least one congenital anomaly identified through manual chart review. Prior to testing, each patient had a list of Human Phenotype Ontology (HPO) terms created. Each patient’s Human Phenotype Ontology (HPO) terms were then mapped to body systems and validated by an internal software (‘Phenobert’). The body systems of interest included musculoskeletal, nervous, genitourinary, digestive, cardiovascular, head/neck/eye/ear, pulmonary, or other. Patients with anomalies in multiple body systems constituted the “More than One System” category. Patients with anomalies isolated to one body system constituted the “Isolated System” category.
From positive genetic diagnoses, diagnostic variants were described by genotype characteristics: Single Nucleotide Variants (SNVs) or Copy Number Variants (CNVs). CNVs were organized as microduplications, microdeletions, or aneuploidies. SNVs were classified as intronic or exonic and further as substitutions, insertions, deletions, or indels, with biological roles analyzed via Panther. Length of stay (LOS) was the primary hospital outcome studied.
Chi-squared, Fisher’s exact, Mantel-Haenszel, and Wilcoxon tests were used to assess statistical differences in the genetic diagnosis rates and LOS among comparison groups.
Results:
The majority of the cohort had anomalies in multiple systems compared to a single system (59% vs. 41%), with a higher genetic diagnosis rate in the "More Than One System" group compared to the “Isolated System” group (32% vs. 21.3%, p=0.04). Of the cohort, 71.4% had anomalies in cardiac, 12.8% in digestive, 29.0% in genitourinary, 29.3% in head/neck/eye/ear, 20.9% in musculoskeletal, 13.8% in nervous, 10.8% in pulmonary, and 5.4% in other. Among the 82 diagnosed patients, 38 CNVs (60.5% microdeletions) and 47 SNVs (87.2% exonic, 63.8% substitutions) were identified. Panther analysis of 41 unique SNV genes showed the top three biological processes were cellular processes, biological regulation, and developmental processes (63.4%).
In the “Isolated System” group, patients with a genetic diagnosis had a longer LOS (median 94 vs. 16 days, p = 0.005). In the “More Than One System” group, the presence or absence of a genetic diagnosis did not affect LOS (median 30.5 vs. 35 days, p > 0.05).
Conclusion:
NICU patients present with a wide range of congenital anomalies across organ systems. While anomalies in multiple organ systems predicted a greater chance of a genetic diagnosis after GS, a significant number of patients with anomalies in one organ system received a genetic diagnosis, highlighting the utility of GS in this population. Genes linked to congenital anomalies in a NICU cohort are often involved in ubiquitous cellular functions expressed across multiple organ systems and cause early symptomatic disease when carrying pathologic variants. While most patients had SNVs, a significant minority had CNVs, highlighting the superiority of GS to detect a variety of genetic mechanisms which result in congenital anomalies.
Patients with congenital anomalies had LOSs extending beyond the neonatal period, with patients having an isolated system anomaly and a genetic diagnosis experiencing the longest hospitalizations. Further study is needed to understand the detectable rate of genetic disease in patients with congenital anomalies and how a genetic diagnosis impacts the NICU stay.