Two novel intronic variants in ABCB4: Clinical features, molecular mechanisms, and literature review

Table 1 Clinical characteristics, ABCB4 variant information, pathological features, and immunohistochemical results of two patients

Patient	Sex	Age of disease	Clinical features	TB (max)	ALT (max)	ALP (max)	GGT (max)	Imaging findings	Gene name	Reference sequence information	Allele 1 (amino acid)	Allele 2 (amino acid)	Zygosity	Inflammation grading and fibrosis stage	Bile ducts	MDR3 IHC
1	Male	21	Chronic cholestasis	29	159	346	1016	Liver cirrhosis, calcification of right lobe of liver, cholecystitis, mild splenomegaly	ABCB4	NG 007118.3	c.2362C>T (p.R788W)	c.537-32G>T (p. ?)	Homozygote	G2-3S2	Reduction	Normal
2	Male	37	Chronic cholestasis, cirrhosis, portal hypertension, and upper gastrointestinal bleeding	21	51	386	219	Liver cirrhosis, splenomegaly, portal vein enlargement, portal hypertension, cholecystitis	ABCB4	NG 007118.3	c.833+2T>C (p. ?)	(-)	Heterozygote	G1-3S4	Absence	Reduction

Biochemical indicators represent the highest test values at initial diagnosis of the patient. Reference values: Total bilirubin (3-19 μmol/L); Alanine aminotransferase (5-40 U/L); Alkaline phosphatase (40-129 U/L); Glutamyl transpeptidase (0-50 U/L). G: Inflammation grading; S: Fibrosis stage; MDR3: Multidrug resistance protein 3; IHC: Immunohistochemistry; TB: Total bilirubin; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; GGT: Glutamyl transpeptidase.

Table 2 Prediction results of bioinformatics software for two intron variants

Variants	Gene name	Reference sequence information	SNP	gnomAD	HGMD	SpliceAI			NNSplice	FSplice	ACMG
						Type	Score	Pre-mRNA position
c.537-32G>T	ABCB4	NG 007118.3	(-)	(-)	(-)	Acceptor loss	0.18	-32 bp	Donor loss	Donor loss	Uncertain significance (PS3 + PM2 + PM4 + PP3)
						Acceptor gain	0.09	-16 bp
c.833+2T>C	ABCB4	NG 007118.3	(-)	(-)	(-)	Donor loss	0.99	2 bp	Donor loss	Donor loss	Uncertain significance (PS3 + PM2 + PM4 + PP3)

SNP: Single nucleotide polymorphism; gnomAD: Genome aggregation database; HGMD: Human gene mutation database; Pre-mRNA: Precursor messenger RNA; ACMG: American college of medical genetics and genomics; PS: Pathogenic strong; PM: Pathogenic moderate; PP: Pathogenic supporting.