Diagnostic Yield of Ultra-rapid Whole Genome Sequencing in the NICU: A Retrospective Review of 324 Cases at a Single Institution
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction:
Standardized criteria for ultra-rapid whole genome sequencing (urWGS) was implemented in our NICU practice in June 2022. We present results of broad-based testing, emphasizing its impact on neonatal diagnosis and management.
Methods:
A retrospective chart review of all NICU patients undergoing urWGS at a tertiary care center between June 2022 and September 2024 was conducted. Eligible participants included neonates admitted to the NICU with any of the following conditions: major or minor congenital anomalies, seizures, hypotonia, neonatal encephalopathy, suspected inborn errors of metabolism, intrauterine growth restriction (IUGR), small for gestational age (SGA), or isolated extreme prematurity (defined as a gestational age below 27 weeks). Any patient with an atypical course as deemed by the neonatal care team was also eligible for urWGS. Patients were excluded if they had a previously confirmed genetic diagnosis explaining their clinical condition or if they exhibited features consistent with a known genetic disorder for which standard diagnostic testing was available.
Results:
A total of 324 neonates met the inclusion criteria, with 239 consenting to genetic testing. Of these, 33 neonates (14%) were identified with a pathogenic or likely pathogenic variant explaining part or all of their phenotype. The genetic findings included 23 monogenic disorders (70%) involving the following genes: PAX2, KIAA0586, FOXF1, AIFM1, RET, BRAF, L1CAM, CCDC22, PKHD1, NIPBL, PACS2, SIN3A, COL12A1, NSD2, MADD, SERPINA1, CYP21A2, KMT2A, MNX1, ACTC1, TFAP2A, and CFTR (in two cases). Additionally, 9 cases (27%) involved chromosomal abnormalities with loci at 4q32.3, 10p, 3q28qter, 11p15.4, Xq26.2q26.3, 22q11, 18p11.3, 18q, and 5p. One case (3%) involved a mitochondrial deletion disorder. None of the 29 neonates with isolated extreme prematurity who consented to testing had a pathogenic or likely pathogenic variant identified.
Among the 33 neonates with pathogenic or likely pathogenic variants, 25 (76%) underwent trio testing, and 8 (24%) underwent duo testing. The indications for urWGS among those with positive findings were diverse, with most neonates presenting with multiple indications. These included major anomalies in 14 cases (41%), IUGR and/ or SGA in 10 cases (29%), minor anomalies in 10 cases (29%), respiratory failure of unknown etiology or unexpected course in 6 cases (18%), hypoxemic neonatal encephalopathy in 3 cases (9%) and skeletal system abnormalities in 2 cases (6%).
Conclusion:
Standardization of early genomic care in the NICU provided timely diagnoses for patients and their families thereby improving provider ability to prognosticate, shorten the diagnostic odyssey, and alter clinical management and surveillance.
Standardized criteria for ultra-rapid whole genome sequencing (urWGS) was implemented in our NICU practice in June 2022. We present results of broad-based testing, emphasizing its impact on neonatal diagnosis and management.
Methods:
A retrospective chart review of all NICU patients undergoing urWGS at a tertiary care center between June 2022 and September 2024 was conducted. Eligible participants included neonates admitted to the NICU with any of the following conditions: major or minor congenital anomalies, seizures, hypotonia, neonatal encephalopathy, suspected inborn errors of metabolism, intrauterine growth restriction (IUGR), small for gestational age (SGA), or isolated extreme prematurity (defined as a gestational age below 27 weeks). Any patient with an atypical course as deemed by the neonatal care team was also eligible for urWGS. Patients were excluded if they had a previously confirmed genetic diagnosis explaining their clinical condition or if they exhibited features consistent with a known genetic disorder for which standard diagnostic testing was available.
Results:
A total of 324 neonates met the inclusion criteria, with 239 consenting to genetic testing. Of these, 33 neonates (14%) were identified with a pathogenic or likely pathogenic variant explaining part or all of their phenotype. The genetic findings included 23 monogenic disorders (70%) involving the following genes: PAX2, KIAA0586, FOXF1, AIFM1, RET, BRAF, L1CAM, CCDC22, PKHD1, NIPBL, PACS2, SIN3A, COL12A1, NSD2, MADD, SERPINA1, CYP21A2, KMT2A, MNX1, ACTC1, TFAP2A, and CFTR (in two cases). Additionally, 9 cases (27%) involved chromosomal abnormalities with loci at 4q32.3, 10p, 3q28qter, 11p15.4, Xq26.2q26.3, 22q11, 18p11.3, 18q, and 5p. One case (3%) involved a mitochondrial deletion disorder. None of the 29 neonates with isolated extreme prematurity who consented to testing had a pathogenic or likely pathogenic variant identified.
Among the 33 neonates with pathogenic or likely pathogenic variants, 25 (76%) underwent trio testing, and 8 (24%) underwent duo testing. The indications for urWGS among those with positive findings were diverse, with most neonates presenting with multiple indications. These included major anomalies in 14 cases (41%), IUGR and/ or SGA in 10 cases (29%), minor anomalies in 10 cases (29%), respiratory failure of unknown etiology or unexpected course in 6 cases (18%), hypoxemic neonatal encephalopathy in 3 cases (9%) and skeletal system abnormalities in 2 cases (6%).
Conclusion:
Standardization of early genomic care in the NICU provided timely diagnoses for patients and their families thereby improving provider ability to prognosticate, shorten the diagnostic odyssey, and alter clinical management and surveillance.