Low phospholipid-associated cholelithiasis and intrahepatic cholestasis of pregnancy are two MDR3-related inherited liver disorders caused by biallelic or monoallelic ABCB4 loss-of-function variants.
We report the first family with autosomal dominant LPAC syndrome due to heterozygosity of the loss of function mutation c.2932T>C in ABCB4, identified by targeted next generation sequencing.
To appreciate the reliability of in silico prediction programs, 1) we confronted them with the assessment in cell models of two ABCB4 variations (E528D and P1161S) identified in patients with low phospholipid-associated cholelithiasis (LPAC); 2) we extended the confrontation to 19 variations that we had previously characterized in cellulo.
The low-phospholipid-associated cholelithiasis syndrome (LPAC; OMIM 171060) is a peculiar form of intrahepatic cholelithiasis occurring in young adults, associated with ABCB4/MDR3 gene sequence variations.
In clinical practice, a comprehensive ABCB4 alteration-screening algorithm will permit the use of ABCB4 genotyping to confirm the diagnosis of LPAC or ICP/CIC, and allow familial testing.
Several mutations of ABCB4 have been identified, which cause cholestatic liver diseases of varying severity including progressive familial intrahepatic cholestasis type 3 (PFIC-3), intrahepatic cholestasis of pregnancy (ICP) and the low phospholipid associated cholelithiasis syndrome (LPAC).
Combined PFIC3 and LPAC phenotype is a rare clinical event, which may be determined by the coexistence of ABCB4 variants related to both phenotypes and also potentially to the ABCB11 variant.
In all cases where the ABCB4 genotyping confirms the diagnosis of LPAC syndrome in young adults, long-term curative or prophylactic therapy with ursodeoxycholic acid (UDCA) should be initiated early to prevent the occurrence or recurrence of the syndrome and its complications.
Mutational analysis of ABCB4, screening for copy number variations by multiplex ligation-dependent probe amplification, genotyping for low expression allele c.1331T>C of ABCB11 and genotyping for variation c.55G>C in ABCG8 previously associated with cholesterol gallstones in adults was performed in 35 pediatric subjects with idiopathic gallstones who fulfilled the clinical criteria for low phospholipid-associated cholelithiasis syndrome (LPAC, OMIM #600803) and in 5 young females with suspected LPAC and their families (5 probands, 15 additional family members).
Combined PFIC3 and LPAC phenotype is a rare clinical event, which may be determined by the coexistence of ABCB4 variants related to both phenotypes and also potentially to the ABCB11 variant.
Conversely, the frequency of rare, heterozygous, potentially pathogenic ABCC2 variants in patients with LPAC, ICP or BRIC did not differ significantly from that of the general population.
Mutational analysis of ABCB4, screening for copy number variations by multiplex ligation-dependent probe amplification, genotyping for low expression allele c.1331T>C of ABCB11 and genotyping for variation c.55G>C in ABCG8 previously associated with cholesterol gallstones in adults was performed in 35 pediatric subjects with idiopathic gallstones who fulfilled the clinical criteria for low phospholipid-associated cholelithiasis syndrome (LPAC, OMIM #600803) and in 5 young females with suspected LPAC and their families (5 probands, 15 additional family members).