Neonatal Cholestasis: Exploring Genetic Causes and Clinical Outcomes

Area of Science:

• Pediatric Hepatology
• Medical Genetics
• Neonatology

Background:

• Neonatal cholestasis is characterized by conjugated hyperbilirubinemia in infants.
• Genetic testing advances aid in identifying specific causes of neonatal cholestasis.
• Understanding genotype-phenotype correlations is crucial for diagnosis and management.

Purpose of the Study:

• To examine the genetic and clinical profiles of neonates with cholestasis.
• To correlate genotypes with phenotypes and assess diagnostic outcomes.
• To evaluate the role of gamma-glutamyl transferase (GGT) in diagnosing cholestasis subtypes.

Main Methods:

• Retrospective review of 378 neonatal cholestasis cases (1997-2024).
• Exclusion of extrahepatic causes and application of genetic testing (cholestasis panel, WES).
• Collection of clinical, biochemical data, including GGT levels.

Main Results:

• Genetic disorders identified in 28.0% of cases, involving genes like ATP8B1, ABCB11, and bile acid synthesis genes.
• GGT levels differentiated cholestasis subtypes: low/normal GGT associated with PFIC1/2 and bile acid synthesis defects; high GGT with PFIC3, alpha-1 antitrypsin deficiency, and cystic fibrosis.
• Increased genetic diagnoses post-2010 (35.5%) compared to pre-2010 (18.2%), with 56.0% consanguinity in genetically diagnosed cases.

Conclusions:

• Genetic diseases are a primary cause of neonatal cholestasis.
• GGT levels are valuable for differentiating cholestasis subtypes.
• Expanded genetic testing improves early diagnosis and personalized management of rare neonatal cholestasis disorders.