Early Diagnosis of Spectrum Liver Disorders by Next Generation Sequencing.

Purpose: The goal of this study was the early diagnosis of spectrum liver disorders, especially those focused on benign recurrent intrahepatic cholestasis and progressive familial intrahepatic cholestasis.

Methods: Fifty patients presenting neonatal cholestasis were evaluated to identify underlying etiologies. Genetic analysis was performed on patients suspected to have syndromic diseases or spectrum liver disorders. Two families with proven spectrum liver disorders were subjected to genetic analyses to confirm the diagnosis and were provided genetic counseling. Whole exome sequencing and Sanger sequencing were performed on the patients and the family members.

Results: Idiopathic or viral hepatitis was diagnosed in 34%, metabolic disease in 20%, total parenteral nutrition induced cholestasis in 16%, extrahepatic biliary atresia in 14%, genetic disease in 10%, neonatal lupus in 2%, congenital syphilis in 2%, and choledochal cyst in 2% of the patients. The patient with progressive familial intrahepatic cholestasis had novel heterozygous mutations of c.11C>G (p.Ser4) and c.1543A>G (p.Asn515Asp). The patient with benign recurrent intrahepatic cholestasis had homozygous mutations of c.1331T>C (p.Val444Ala) and heterozygous, c.3084A>G (p.Ala1028Ala). Genetic confirmation of spectrum liver disorder led to early liver transplantation in the progressive familial intrahepatic cholestasis patient. In addition, the atypically severe benign recurrent intrahepatic cholestasis patient was able to avoid unnecessary liver transplantation after genetic analysis.

Conclusion: spectrum liver disorders can be clinically indistinguishable as they share similar characteristics related to acute episodes. A comprehensive genetic analysis will facilitate optimal diagnosis and treatment.