Bile salt export pump deficiency disease: two novel, late onset, ABCB11 mutations identified by next generation...

Area of Science:

• Genetics
• Hepatology
• Molecular Biology

Background:

• Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC) are genetic cholestatic liver diseases in children.
• PFIC2 is linked to mutations in the ABCB11 gene, encoding the bile salt export pump (BSEP).
• Current diagnostic methods are costly and limited to specialized centers.

Observation:

• This study applied next-generation sequencing (NGS) for parallel gene analysis in diagnosing familial intrahepatic cholestasis.
• Two patients with severe, unexplained cholestatic disease were investigated.
• NGS identified molecular defects in the ABCB11 gene in both probands.

Findings:

• The first patient presented compound heterozygosity for a novel frameshift mutation (p.Ser1100GlnfsX38) and a missense variant (p.Glu135Lys).
• The second patient, whose condition was exacerbated by contraceptive therapy, showed homozygosity for a novel missense variant (p.Ala523Gly).
• These identified mutations appear to result in a milder, later-onset disease phenotype.

Implications:

• NGS offers a more accessible and cost-effective diagnostic approach for PFIC and BRIC.
• The identified ABCB11 mutations represent potential intermediate forms between BRIC and PFIC.
• Understanding these genetic variations can improve diagnosis and management of pediatric cholestatic liver diseases.