Ultra‐rapid whole genome sequencing: A paradigm shift in the pre‐transplant evaluation of neonatal acute liver failure

Abstract

To the editor, Neonatal acute liver failure (NALF) is an ominous disorder resulting from severe hepatocellular injury and manifesting as rapid deterioration of liver function. Common etiologies of NALF include gestational alloimmune liver disease (GALD), viral infection (VI), familial hemophagocytic lymphohistiocytosis (fHLH), mitochondrial hepatopathy (MH), toxic metabolic hepatopathy (TMH), and genetic cholestasis (GC), [1] although most cases of NALF remain idiopathic. [2] Evaluation for liver transplantation (LT) in cases of NALF requires accurate and timely diagnoses to identify conditions appropriate for LT while excluding those where targeted therapies or poor prognosis contradict LT. Recent advances in nextgeneration sequencing technology have made such a rapid diagnosis possible.Standard sequential genetic testing, including karyotype, fluorescence in situ hybridization (FISH), microarray, targeted gene testing, and whole exome sequencing (WES), can collectively take several weeks to months. In contrast, ultra-rapid whole genome sequencing (urWGS) can yield a molecular diagnosis in as little as 12 h and typically provides actionable results within 3 days. [3] urWGS detects all levels of genomic variation from single nucleotide variants (SNVs) to structural variants. Compared with typical genetic evaluation, urWGS has a superior diagnostic rate, clinical utility, and cost-efficiency as first-line testing for neonates who are critically ill.

Neonatal Diagnosis of Alveolar Capillary Dysplasia via Rapid Genomic Sequencing: A New Gold Standard?

“…rGS has demonstrated improved diagnostic rate and clinical utility as compared to other forms of genetic testing with reduced overall costs of care [9,10]. Our group has also shown the utility of rapid genome sequencing as first-line testing in neonatal acute liver failure, for which the gold standard diagnostic test had previously been liver biopsy, which is similarly often unfeasible in critically ill neonates [11]. While rGS represents an important step forward in timely and comprehensive diagnosis of severe neonatal hypoxemic respiratory failure, determining pathogenic significance of variants not previously described, as with other types of genetic testing, remains a challenge.…”

Neonatal hemophagocytic lymphohistiocytosis: A meta‐analysis of 205 cases

“…The differential diagnosis for NALF includes nHLH, gestational alloimmune liver disease (GALD), sepsis, viral infections, metabolic hepatology, transient abnormal myelopoiesis, and hypoperfusion injury. 8,9 In an epidemiologic analysis, Balakumar and colleagues (2022) found that liver failure occurred in 35% of nHLH cases and that liver failure was the only organ dysfunction independently associated with increased mortality on multivariable analysis. 7 The epidemiologic methodology used by Balakumar et al ( 2022) utilized ICD-9 and ICD-10 codes and, similar to other studies that use large databases, was limited by coding accuracy.…”

“…The clinical presentation of nHLH is diverse and can include fever, hydrops, neonatal acute liver failure (NALF), cytopenias, respiratory distress, and encephalopathy—all of which have their own unique differential diagnoses that may be more common causes of critical illness in neonates 6 . For example, the differential diagnosis of NALF includes nHLH, infection, gestational alloimmune liver disease, liver ischemia, metabolic hepatology, and transient abnormal myelopoiesis 8,9 . A proper understanding and index of suspicion of nHLH is clinically necessary for pediatric hematologists/oncologists and intensivists to diagnose nHLH.…”

“…6 For example, the differential diagnosis of NALF includes nHLH, infection, gestational alloimmune liver disease, liver ischemia, metabolic hepatology, and transient abnormal myelopoiesis. 8,9 A proper understanding and index of suspicion of nHLH is clinically necessary for pediatric hematologists/oncologists and intensivists to diagnose nHLH.…”