Whole exome sequencing analysis revealed an inherited AKR1D1 defect in twins with infantile intrahepatic cholestasis

Neonatal cholestasis comprises a variety of disorders, including inherited defects in bile acid (BA) synthesis, conjugation or transport. A family presented with twins at the age of 2 months with elevated transaminases, hyperbilirubinemia, and infantile cholestasis. The mother had experienced an episode of cholestasis after ingestion of ecstasy. Whole Exome Sequencing (WES) was performed from both parents and the twins.

For data analysis, an autosomal recessive disorder was assumed. As the parents were not consanguine, compound heterozygosity seemed plausible. WES revealed 40,000 genetic variants for each twin. Eliminating all synonymous variants, over 10,000 variants per patient remained. For further analysis, heterozygous variants were selected (6,300 variants remaining) and filtered for heterozygosity in the parents (4,400 variant remaining). Next, genes with more than one variant were selected, leaving us with 2,300 variants, which were filtered for minor allele frequencies of < 1% and potentially pathogenicity by in silico prediction using PolyPhen2 (50 variants remaining). Of these, both children showed the same two variants within the AKR1D1 gene, whereas each parent had one of these variants. DNA analysis for the healthy sister revealed homozygosity for the wildtype allele at both positions.

AKR1D1 variants are associated with delta(4)-oxosteroid-5beta-reductase deficiency, resulting in a lack of primary BA and an accumulation of atypical 3-oxo-delta-4 and allo-bile acids, which can be measured in urine. These abnormalities were present in these patients and cholic acid supplementation was initiated and led to improvement of liver function in both children.

This case of a family with an inherited bile acid synthesis deficiency illustrates the importance of a combined interdisciplinary clinical, genetic, and biochemical analysis for diagnostics of infantile cholestasis.