Congenital Bile Acid Synthesis Defect Type 2 via the AKR1D1 Gene

Congenital bile acid synthesis defect type 2 (CBAS2) is a progressive liver disease of neonatal onset characterized by cholestasis (Lemonde et al. 2003; Ueki et al. 2009). Due to impaired bile acid synthesis, within the first weeks of life, affected infants start to present with malabsorption of lipids and lipid-soluble vitamins from the gastrointestinal tract. Clinical features include failure to thrive, jaundice, steatorrhea, hepatomegaly, cirrhosis, rickets and splenomegaly.

Recessive AKR1D1 pathogenic variants cause congenital bile acid synthesis defect type 2 (Lemonde et al. 2003; Ueki et al. 2009). The AKR1D1 gene (9 coding exons; also known as SRD5B1) encodes the steroid 5-beta-reductase, which is responsible for the catalysis of the 5-beta-reduction of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure. Genetic defects of AKR1D1 found to date include missense, nonsense, and small deletions (Human Gene Mutation Database). No large deletions and duplications have been reported.

Detection rate of pathogenic variants in the AKR1D1 gene in a large cohort of patients with congenital bile acid synthesis defect type 2 is unknown in the literature because only a limited number of cases have been reported. However, mutation detection rate is expected to be high if patients are strongly indicated both clinically and biochemically.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the AKR1D1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.