Genetic variation features of neonatal hyperbilirubinemia caused by inherited diseases

Table 1 Demographic and clinical characteristics of the study population, n (%)

Variable	Patient cohorts (n = 105)
Sex
Female	43
Male	54
Gestational age (weeks)	38 ± 2
birth weight (kg)	3.25 ± 0.82 (2.01-4.10)
Age of onset (days)
1-3 days	59
4-7 days	11
≥ 8 days	6
Feeding pattern
Full breastfeeding	73
Mix feeding	24
Premature birth
Yes	9
No	87

Table 2 List of pathogenic/likely pathogenic variants in patients

Gene	Cytogenetic location	Mutation variant	Amino acid variant	Type of gene	Allele frequency
Uridine 5'-diphospho-glucuronosyltransferase 1A1	Chr2: 234669144	C.211G>A	P.Gly71Arg	Het/hom	0.152
	Chr2: 234676872	C.1091C>T	P.Pro364 Leu	Het	0.012
	Chr2: 234681059	C.1456T>G	P.Tyr486Asp	PAT	0.001
	Chr2: 234680955	C.1352C>T	P.Pro451 Leu	Het	0.005
Na+/taurocholate cotransporting polypeptide Ntcp	Chr14: 70245193	C.800C>T	P.Ser267Phe	Het/hom	0.078
heterozygous 851del4 mutation	Chr7: 95818684	C.852_855delTATG	P.Met285ProfsTer2	Het	0.004
	Chr7: 95813702	C.1064G>A	P.Arg355Gln	Het	3.48E-04
	Chr7: 95775896	C.1424G>A	P.Arg475Gln	Het	-
	Chr7: 95751240	C.1638_1660dup	P.Ala554GlyfsTer17	Het	0.0013
ATP 7B	Chr13: 52515283	C.3490G>A	P.Asp1164Asn	Het	-
	Chr13: 52524503	C.2480G>A	P.Arg827Gln	Het	5.80E-4
	Chr13: 52523859	C.2804C>T	P.Thr935Met	Het	0.002
	Chr13: 52548886	C.470G>T	P.Cys157Phe	Het	-
	Chr13: 52524515	C.2468A>G	P.Glu823Gly	Het	1.16E-4
	Chr13: 52534313	C.2092A>C	P.Ile698 Leu	Het	-
Glucose-6-phosphate dehydrogenase	ChrX: 153774276	C.185A>G	P.His62Arg	Hemi	0.002
	ChrX: 153763476	C.482G>T	P.Gly161Val	Het	6.03E-4
	ChrX: 153760484	C.1466G>T	P.Arg489 Leu	Het	0.008
	ChrX: 153760472	C.1478G>A	P.Arg493His	Hemi	0.005
Beta-globin gene	Chr11: 5246931	C.341T>A	P.Val114Glu	Het	2.32E-4
Cytochrome P450, Family 7, Subfamily B, Polypeptide 1	Chr8: 65536958	C.259+2T>C		Het	1.16E-4
ATP-binding cassette subfamily C member 2	Chr10: 101552060	C.277C>T	P.Gln93Ter	Het	1.16E-4
Jagged 1	Chr20: 10622442	C.2671G>A	P.Ala891Thr	Het	-
Niemann-Pick type C 1	Chr18: 21116653	C.3229C>T	P.Arg1077Ter	Het	-
Farnesoid X receptor	Chr12: 100926359	C.569T>A	P.Met190 Lys	Het	-
3β-hydroxy-Δ5-C27-steroid oxidoreductase	Chr16: 30998260	C.631C>T	P.Arg211Cys	Het	-
	Chr18: 21123451	C.2213C>A	P.Ser738Ter	Het	1.16E-4
	Chr18: 21152082	C.243G>C	P.Gln81His	Het	-
ATP 8B1	Chr18: 55351421	C.1477G>A	P.Val493Ile	Het	7.11E-4
	Chr20: 10629285	C.1481A>G	P.Asn494Ser	Het	-
Trihydroxycoprostanoyl-CoA oxidase	Chr3: 58512313	C.1226G>A	P.Arg409His	Het	0.002
	Chr3: 58508322	C.1533A>G	P.Ile511Met	Het	5.78E-4
SMase gene	Chr11: 6412666	C.371T>G	P.Leu124Arg	Het	3.47E-4
	Chr10: 101604163	C.3928C>G	P.Arg1310Gly	Het	-
	Chr12: 100904723	C.247C>G	P.Pro83Ala	Het	5.78E-04
	Chr10: 101590078	C.2643_2645delAGA	P.Glu881del	Het	-
ATP-binding cassette transporters	Chr2: 169830310	C.1349T>C	P.Met450Thr	Het	4.65E-4
	Chr11: 5247153	C.316-197C>T		Het	-
ATP-binding cassette sub-family D member 3	Chr1: 94933490	C.262C>T	P.Leu88Phe	Het	0.001
	Chr18: 21136571	C.962C>T	P.Ala321Val	Het	3.67E-4
	Chr20: 10623197	C.2511T>G	P.Asp837Glu	Het	-

ATP: Adenosine triphosphatase.

Table 3 The correlation between clinical characteristics and total serum bilirubin levels

	Hyperbilirubinemia
Factors	Total serum bilirubin ≥ 342 μmol/L	Total serum bilirubin < 342 μmol/L	P value
Gender
Female	17	26	0.67
Male	18	36
Exclusive breastfeeding
Yes	31	42	0.027
No	4	20
Gestational age (week)	38.9 ± 1.26	38.6 ± 1.43	0.170
Birth weight (kg)	3.19 ± 0.41	3.16 ± 0.41	0.38
P
Yes	2	7	0.48
No	33	54

Table 4 Gene mutation analysis between high and low total serum bilirubin groups

	Hyperbilirubinemia
Mutation	Total serum bilirubin ≥ 342 µmol/L	Total serum bilirubin < 342 μmol/L	P value
Uridine 5'-diphospho-glucuronosyltransferase 1A1
G/A	32	11	0.32
C/T	4	3
T/G	1	1
Na+/taurocholate cotransporting polypeptide Ntcp
C/T	6	7	NA
Heterozygous 851del4 mutation
C.852_855delTATG	2	3	0.57
C.1638_1660dup	0	1
G/A	0	1
Adenosine triphosphatase 7B
G/T	1	0	0.26
A/C	1	0
G/A	0	1
C/T	0	1
Glucose-6-phosphate dehydrogenase
G/T	1	2	0.32
G/A	1	0
A/G	0	1