Mutation spectrum and biochemical features in infants with neonatal Dubin-Johnson syndrome

Abstract

Background: Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder presenting as isolated direct hyperbilirubinemia.DJS is rarely diagnosed in the neonatal period. The purpose of this study was to clarify the clinical features of neonatal DJS and to analyze the genetic mutation of adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2). Methods: From 2013 to 2018, 135 infants with neonatal cholestasis at Seoul National University Hospital were enrolled. Genetic analysis was performed by neonatal cholestasis gene panel. To clarify the characteristics of neonatal DJS, the clinical and laboratory results of 6 DJS infants and 129 infants with neonatal cholestasis from other causes were compared. Results: A total of 8 different ABCC2 variants were identified among the 12 alleles of DJS. The most common variant was p.Arg768Trp (33.4%), followed by p.Arg100Ter (16.8%). Three novel variants were identified (p.Gly693Glu, p.Thr394Arg, and p.Asn718Ser). Aspartate transaminase (AST) and alanine transaminase (ALT) levels were significantly lower in infants with DJS than in infants with neonatal cholestasis from other causes. Direct bilirubin and total bilirubin were significantly higher in the infants with DJS. Conclusions: We found three novel variants in 6 Korean infants with DJS. When AST and ALT levels are normal in infants with neonatal cholestasis, genetic analysis of ABCC2 permits an accurate diagnosis.

Clinical, Biochemical, and Molecular Characterization of Neonatal-Onset Dubin–Johnson Syndrome in a Large Case Series From the Arabs

“…The clinical phenotype and biochemical profile (normal or elevated GGT, and high total serum bile acids) of neonatal-onset DJS overlap with a broad list of causes of NC, which makes the identification of DJS challenging to clinicians. Notably, some neonates with DJS present with acholic stool and high-GGT cholestasis, a phenotype similar to neonates with BA, and might undergo invasive procedures (liver biopsy and intraoperative cholangiography), a scenario that happened frequently in some reported case series ( 9 , 10 , 19 ) and in three of our patients as well. Hence, early consideration and prompt diagnosis of DJS is a very important step in the work up of a neonate with cholestasis to avoid subjecting a patient with a benign prognosis to unnecessary invasive and costly evaluation.…”

“…This variant is unique to the Saudi population and found in several major tribes in the center of the Arabian Peninsula with a cumulative carrier frequency of 0.0051 (one in 195), strongly suggesting that this variant is of common ancestral origin, which accounted for the observed cluster. Two of the four ABCC2 gene variants identified in two families from our study cohort [c.3258+1G>A and c.2439G>C (p.Lys813Asn)] were previously reported in the Asian populations ( 9 , 10 ). The prevalence of consanguineous marriage in Saudi Arabia is almost 60% ( 24 ), which presents a major risk factor for autosomal recessive diseases.…”

“…The third tool that was frequently employed to diagnose DJS phenotype, before the first molecular characterization of ABCC2 gene in 1997 ( 1 ), is liver biopsy. The characteristic histopathological finding of melanin-like pigment deposits in hepatocytes is uncommon in neonates compared with adults ( 9 , 10 ). Thus, the low diagnostic yield and invasiveness of the procedure make liver biopsy an unfavorable diagnostic tool of neonatal-onset DJS, particularly in the era of the advanced molecular genetics and availability of non-invasive methods.…”

“…These variants vary across different ethnic groups. The p.R768W variant occurred with a high frequency in the Japanese population ( 9 ), while the p.Arg768Trp is the most common variant in the Korean population ( 10 ), and the p.R393W and p.Y1275X variants are known disease-causing variants in Taiwan ( 11 ). Some variants are unique to the Jewish population of Iranian and Moroccan origins (p.I1173F and p.R1150H, respectively) ( 3 ).…”

Neonatal Dubin-Johnson Syndrome and its Differentiation from Biliary Atresia

“…Twenty-two of the variations we observed had been previously reported, 10,11,[13][14][15][16] and thirty-three were novel (Table 2). Of the novel variants, six were canonical splicing variants, two were noncanonical splicing variants, five were nonsense variants, thirteen were missense variants, and seven were frameshift variants.…”