UGT1A1-related disorders in Bahrain: A genetic and clinical overview of Crigler-Najjar and Gilbert syndromes

doi:10.5409/wjcp.121263

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World Journal of Clinical Pediatrics

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Retrospective Cohort Study

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World J Clin Pediatr. Dec 9, 2026; 15(4): 121263
Published online Dec 9, 2026. doi: 10.5409/wjcp.121263

Table 1 Clinical characteristics of patients with UGT1A1-related disorders, n (%)/medians (interquartile range)

Clinical characteristics	Total, n = 35 (100)	CNS-I, n = 1 (2.9)	CNS-II, n = 7 (20.0)	GS, n = 27 (77.1)	P value¹
Demographics
Sex					1.000²
Male	27 (77.1)	1 (100)	6 (85.7)	20 (74.1)
Female	8 (22.9)	0 (0.0)	1 (14.3)	7 (25.9)
Nationality					0.511²
Bahraini	32 (91.4)	1 (100)	6 (85.7)	25 (92.6)
Non-Bahraini	3 (8.6)	0 (0.0)	1 (14.3)	2 (7.4)
Age at the time of diagnosis (years)	13.1 (9.0-16.8)	0.58	11.3 (0.3-16.8)	13.4 (11.9-16.9)	0.110³
Age at the time of study (years)	15.2 (13.3-19.0)	21.4	15.3 (14.2-19.0)	14.9 (13.1-18.5)	0.782³
Gestational age (n = 30)					1.000²
Term	26 (86.7)	1 (100)	6 (85.7)	19/22 (86.4)
Preterm	4 (13.3)	0 (0.0)	1 (14.3)	3/22 (13.6)
Birth weight (n = 27)	3 (2.5-3.5)	3.0	3.0 (2.5-3.5)	3.0 (2.5-3.5)	0.954³
Family history of prolonged jaundice	9 (25.7)	0 (0.0)	4 (57.1)	5 (18.5)	0.061²
Parental consanguinity	14 (40.0)	1 (100)	4 (57.1)	9 (33.3)	0.387²
Clinical presentations
Jaundice	35 (100)	1 (100)	7 (100)	27 (100)	N/A
Changes in urine color	13 (37.1)	0 (0.0)	2 (28.6)	11 (40.7)	0.682²
Pruritus	10 (28.6)	0 (0.0)	3 (42.9)	7 (25.9)	0.394²
Changes in stool color	5 (14.3)	0 (0.0)	1 (14.3)	4 (14.8)	1.000²
Splenomegaly	13 (37.1)	0 (0.0)	2 (28.6)	11 (40.7)	0.682²
Hepatomegaly	7 (20.0)	0 (0.0)	1 (14.3)	6 (22.2)	1.000²
Associated diseases
G6PD deficiency	17 (48.6)	1 (100)	4 (57.1)	12 (44.4)	0.681²
Sickle cell disease	14 (40.0)	0 (0.0)	2 (28.6)	12 (44.4)	0.672²
Alpha-thalassemia	5 (14.3)	1 (100)	1 (14.3)	3 (11.1)	1.000²
Sickle-thalassemia	3 (8.6)	0 (0.0)	0 (0.0)	3 (11.1)	1.000²
Sickle cell trait	3 (8.6)	0 (0.0)	1 (14.3)	2 (7.4)	0.511²
Beta-thalassemia major	2 (5.7)	0 (0.0)	0 (0.0)	2 (7.4)	1.000²
Beta-thalassemia trait	1 (2.9)	0 (0.0)	0 (0.0)	1 (3.7)	1.000²
Eczema	10 (28.6)	0 (0.0)	3 (42.9)	7 (25.9)	0.394²

¹After excluding the single patient with Crigler-Najjar syndrome-I, the P values represent the differences between Crigler-Najjar syndrome-II and Gilbert syndrome groups only. Boldface indicates statistically significant difference with P < 0.05.

²Fisher’s exact test.

³Mann-Whitney U test.

CNS: Crigler-Najjar syndrome; GS: Gilbert syndrome; N/A: Not applicable; G6PD: Glucose-6-phosphate dehydrogenase.

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Table 2 Biochemical parameters of patients with UGT1A1-related disorders, n (%)/median (interquartile range)

Biochemical parameters	Normal range	Total, n = 35 (100)	CNS-I, n = 1 (2.9)	CNS-II, n = 7 (20.0)	GS, n = 27 (77.1)	P value¹ (95%CI)
Hemoglobin (g/dL)	12.0-14.5	10.9 ± 2.1	10.9	11.0 ± 1.7	10.9 ± 2.2	0.955 (-1.8, 1.9)²
Hematocrit (%)	33-45	33.2 ± 5.8	32.1	33.9 ± 3.8	33.1 ± 6.4	0.721 (-4.3, 6.1)²
RBC (× 10¹²/L)	3.9-5.2	4.4 ± 0.9	5.3	4.5 ± 0.9	4.4 ± 0.9	0.732 (-0.7, 0.9)²
Reticulocyte (%) (n = 32)	0.5-1.5	2.7 (1.9-5.6)	1.9	1.8 (1.1-6.1) (n = 6)	3.0 (2.1-5.3) (n = 25)	0.368³
Platelet count (× 10⁹/L)	150-400	286 (221-396)	263	331 (259-403)	282 (221-381)	0.338³
Total protein (g/L)	57-82	74 ± 5.9	62.0	70.3 ± 3.9	74.8 ± 5.9	0.086 (-9.1, 0.62)²
Serum albumin (g/L)	38-54	44.5 ± 3.4	37.0	44.1 ± 5.3	44.7 ± 2.9	0.706 (-3.6, 2.4)²
Total bilirubin at presentation (μmol/L)	5-21	89.7 ± 52.7	409	105.3 ± 46.2	88.2 ± 53.8	0.447 (-28.2, 62.5)²
Direct bilirubin (μmol/L)	≤ 5.0	14 (10-18)	4.0	15 (8-16)	14 (11-19)	0.468³
Indirect bilirubin at presentation (μmol/L)	≤ 18	72 (24-126)	405	95 (40-122)	68 (23-126)	0.194³
Maximum total bilirubin (μmol/L)	5-21	147 (98-228)	409	188 (121-227)	133 (91-238)	0.406³
Maximum indirect bilirubin (μmol/L)	≤ 18	122.7 (82-210)	405	173 (109-210)	119 (67-182)	0.297³
ALP (U/L)	142-335	185 (132-254)	246	254 (132-343)	180 (118-204)	0.383³
ALT (U/L)	≤ 33	17 (12-25)	106	17 (11-25)	17 (12-22)	0.983³
GGT (U/L)	≤ 38	11 (8-20)	20	15 (7-38)	10 (9-16)	0.932³
Vitamin D level (nmol/L) (n = 27)	> 50	31.3 ± 11.5	48	31.7 ± 6.0 (n = 3)	30.5 ± 11.8 (n = 23)	0.871 (-13.3, 15.6)²

²Student’s t-test.

³Mann-Whitney U test.

CNS: Crigler-Najjar syndrome; GS: Gilbert syndrome; RBC: Red blood cells; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; GGT: Gamma-glutamyl transferase.

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Table 3 Genetic variants of patients with UGT1A1-related disorders, n (%)

Polymorphism	Zygosity	UGT1A1 variant	Location	Zygosity	Classification	Total, n = 35 (100)
CNS-I						1 (2.9)
(TA)7/7	Homozygous	c.1070A>G p.(Gln357Arg)[2,7,22]	Exon 3	Homozygous	Pathogenic	1 (2.9)
CNS-II						7 (20.0)
(TA)7/7	Homozygous	c.907G>A p.(Val303Met)[24]	Exon 2	Homozygous	VUS	2 (5.7)
(TA)7/7	Heterozygous	c.161G>A p.(Gly54Val)	Exon 1	Heterozygous	VUS	1 (2.9)
(TA)7/7	Homozygous	c.674T>G p.(Val225Gly)[23]	Exon 1	Homozygous	LP	1 (2.9)
		c.907G>A p.(Val303Met)[24]		Homozygous	VUS	1 (2.9)
(TA)7/7	Homozygous	c.674T>G p.(Val225Gly)[23]	Exon 1	Homozygous	LP	1 (2.9)
		c.907G>A p.(Val303Met)[24]		Heterozygous	VUS	1 (2.9)
(TA)7/7	Homozygous	c.674T>G p.(Val225Gly)[23]	Exon 1	Heterozygous	LP	1 (2.9)
		c.907G>A p.(Val303Met)[24]		Heterozygous	VUS	1 (2.9)
(TA)7/7	Homozygous	c.1070A>G p.(Gln357Arg)[2,7,22]	Exon 3	Heterozygous	Pathogenic	1 (2.9)
GS						27 (77.1)
(TA)7/7	Homozygous					24 (68.6)
(TA)7/8	Compound heterozygous					2 (5.7)
(TA)7/7	Homozygous	c.-3275T>G[25]		Homozygous	VUS	1 (2.9)

CNS: Crigler-Najjar syndrome; GS: Gilbert syndrome; LP: Likely pathogenic; VUS: Variant of unknown significance.

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Table 4 Management of patients with UGT1A1-related disorders, n (%)

Patient management	Total, n = 35 (100)	CNS-I, n = 1 (2.9)	CNS-II, n = 7 (20.0)	GS, n = 27 (77.1)
Medications
Phenobarbital	20 (57.1)	1 (100)	6 (85.7)	13 (48.1)
Folic acid	20 (57.1)	1 (100)	3 (42.9)	16 (59.3)
Vitamin D supplementation	20 (57.1)	1 (100)	1 (14.3)	18 (66.7)
Hydroxyurea	16 (45.7)	0 (0.0)	2 (28.6)	14 (51.9)
Ursodeoxycholic acid	13 (37.1)	0 (0.0)	1 (14.3)	12 (44.4)
Other medications¹	16 (45.7)	1 (100)	1 (14.3)	14 (51.9)
Medical/surgical procedures
Blood transfusion	15 (42.9)	1 (100)	2 (28.6)	12 (44.4)
Phototherapy	13/31 (41.9)	1 (100)	4/6 (66.7)	8/24 (33.3)
Cholecystectomy	8 (22.9)	0 (0.0)	2 (28.6)	6 (22.2)
Splenectomy	6 (17.1)	0 (0.0)	1 (14.3)	5 (18.5)
Liver transplantation	1 (2.9)	1 (100)	0 (0.0)	0 (0.0)

¹Crigler-Najjar syndrome-I: Tacrolimus, magnesium supplement, and iron supplement (n = 1); Crigler-Najjar syndrome-II: Prophylactic antibiotics (n = 1); Gilbert syndrome: Prophylactic antibiotics and aspirin (n = 5, each), iron chelation (n = 4), laxative (n = 4), calcium supplement (n = 3); omeprazole (n = 2), rifampicin, erythromycin, multivitamins, fat-soluble vitamins, pancreatic enzyme replacement therapy (Creon), L-thyroxin, growth hormone, testosterone, warfarin, antihypertensives, frusemide, inhaled steroids, and bronchodilators (n = 1, each).

CNS: Crigler-Najjar syndrome; GS: Gilbert syndrome.

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Table 5 Summary of the main features of UGT1A1-related disorders

Main features	CNS-I	CNS-II	GS
Prevalence	Ultra-rare[26]	Unclear (no record)	Prevalent (8%-10%)[5,6,8,9]
UGT1A1 enzyme activity	0%[5]	< 10%[6]	10%-30%[9]
Age at presentation	Neonatal period[1,28]	Infancy or childhood[33]	Adolescence or adulthood[8]
Triggers of jaundice	None	Fasting, illness or stress[4,6]	Fasting, illness, or stress[5,8]
Clinical severity; unconjugated bilirubin range (µmol/L)	Severe[28,33]; 340-850[33]	Moderate[33]; 85-340[33]	Mild[8,33]; < 85[33]
Kernicterus risk	High[1,3,6,10]	Low[7]	None[5]
Medical therapy	Phototherapy[1,26], plasma phoresies[1,26], or liver transplantation[3,11]	Phenobarbital[33]	No treatment needed[5]
Outcome	Poor if not treated[1,3,10]	Good[33]	Excellent[6]

CNS: Crigler-Najjar syndrome; GS: Gilbert syndrome.

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Table 6 Summary of UGT1A1-related disorders studies published from neighboring countries to Bahrain and worldwide

Country	Ref.	n	Sex (M:F)	Promotor variant	UGT1A1 mutation	Zygosity	Location	Additional variant	Zygosity
CNS-I
Saudi Arabia	Nazer et al[1], 1998	12	8:4	NR	NR	NR	NR	NR	NR
Kuwait	Koshy et al[2], 2004	2	0:2	(TA)7/7	1070A>G (p.Gln357Arg)	+/-	Exon 3	NR	NR
Turkey	Ozçay et al[3], 2009	4	NR	NR	NR	NR	NR	NR	NR
Tunisia	Abdellaoui et al[7], 2022	12/17	NR	(TA)7/7	c.1070A>G (p.Gln357Arg)	+/+	Exon 3	NR	NR
		5/17	NR	(TA)8/8	c.1070A>G (p.Gln357Arg)	+/+	Exon 3	NR	NR
Tunisia	Petit et al[22], 2008	23	6:17	(TA)7/7	c.1070A>G (p.Gln357Arg)	+/+	Exon 3	NR	NR
Germany	Schröder et al[14], 2021	12/13	10:3	NR	NR	NR	NR	NR	NR
Netherlands	Hafkamp et al[15], 2007	7/16	5:11	NR	NR	NR	NR	NR	NR
China	Li et al[4], 2015	6	6:2	(TA)7/7	c.221G>A (p.Gly71Arg)	+/+	Exon 1	NR	NR
Croatia	Kovačić Perica et al[28], 2023	2/8	4:4	(TA)7/7	c.717_718delAG (p.Q239fs*256)	NR	Exon 1	NR	NR
		1/8		(TA)7/7	c.722_723delAG (p.Glu241Glyfs*16)	NR	Exon 1	NR	NR
		2/8		(TA)6/6	c.1021C>T (p.Arg341*)	NR	Exon 3	NR	NR
		1/8		N/A	c.1021C>T (p.Arg341*)	NR	Exon 3	NR	NR
		1/8		Not performed	Confirmed by chromatographic bile analysis	NR	NR	NR	NR
		1/8		Lost result	NR	NR	NR	NR	NR
Iran	Mohammadi Asl et al[20], 2013	4/12	2:2	NR	c.238_240delAG	+/+	Exon 1	NR	NR
					c.479T>A (p.Val160Glu)	+/+	Exon 1	NR	NR
Iran	Maruo et al[23], 2015	2	1:1	NR	c.381insGG (p.C127Wfs*23)	+/+	Exon 1	NR	NR
United States	Strauss et al[16], 2006	17/20	NR	NR	c.222C>A (p.Tyr74Ter)	+/+	Exon 1	NR	NR
		1/20			c.1069C>T (p.Gln357Ter)	+/+	Exon 3	NR	NR
		1/20			c.1305-1G>A, c.877_890delinsT	+/-, +/-	Exon 4, Exon 2	NR	NR
CNS-II
Japan	Maruo et al[31], 2006	1	1:0	(TA)7/7	c.115C>G (p.His39Asp)	+/+	Exon 1	NR	NR
Iran	Maruo et al[23], 2015	1	1:0	(TA)7/7	c.381insGG (p.C127Wfs*23)	+/-	Exon 1	c.674T>G (p.Val225Gly)	+/- (Exon 1)
France	Labrune et al[32], 2002	1	0:1	(TA)8/8	c.1213A>G (p.Asn400Asp)	+/+	Exon 4	NR	NR
Germany	Schröder et al[14], 2021	1/13	10:3	NR	NR	NR	NR	NR	NR
Netherlands	Hafkamp et al[15], 2007	9/16	5:11	NR	NR	NR	NR	NR	NR
China	Li et al[4], 2015	1/11	8:3	NR	c.211G>A (p.Gly71Arg)	+/+	NR	c.1456T>G (p.Tyr486Asp)	+/+
		1/11			c.211G>A (p.Gly71Arg)	+/-	NR	c.1456T>G (p.Tyr486Asp)	+/+
		1/11			c.1091C>T (p.Pro364 Leu)	+/+	NR	c.-40_-39insTA	+/-
		1/11			c.1456T>G (p.Tyr486Asp)	+/-	NR	c.1253del (p.Met418Argfs*6)	+/-
		2/11			c.715C>T (p.Gln239*)	+/-	NR	c.-40_-39insTA	+/+
		1/11			c.1091C>T (p.Pro364 Leu)	+/-	NR	c.211G>A (p.Gly71Arg)	+/-
		1/11			c.211G>A (p.Gly71Arg)	+/-	NR	c.-40_-39insTA	+/-
							NR	c.-3279T>G	+/-
		2/11			c.211G>A (p.Gly71Arg)	+/-	NR	c.-3345delC	+/-
		1/11			c.211G>A (p.Gly71Arg)	+/-	NR	NR	NR
China	Wu et al[8], 2024	78/310	50:28	(TA)7/7 (TA)7/6 (TA)6/6	c.211G>A (p.Gly71Arg)	+/+, +/-	Exon 1	NR	NR
Japan	Yamamoto et al[13], 1998	5/7	3:4	(TA)7/7	c.211G>A (p.Gly71Arg)	+/+	Exon 1	c.1456T>G (p.Tyr486Asp)	+/+ (Exon 5)
		1/7		(TA)7/7	c.625C>T (p.Arg209Trp)	+/+	Exon 1	NR	NR
		1/7		(TA)7/7	c.686C>A (p.Pro229Gln)	+/-	Exon 1	NR	NR
Taiwan	Huang et al[33], 2006	1/3	0:1	NR	c.479T>A (p.Val160Glu)	+/+	Exon 1	NR	NR
		1/3	0:1	NR	c.610A>G (p.Met204Val)	+/+	Exon 1	NR	NR
		1/3	0:1	NR	c.1456T>G (p.Tyr486Asp)	+/+	Exon 5	c.211G>A (p.Gly71Arg)	+/-
Iran	Mohammadi Asl et al[20], 2013	8/12	4:4	NR	c.238_240delAG	+/+	Exon 1	NR	NR
					c.479T>A (p.Val160Glu)	+/+	Exon 1	NR	NR
GS
Africa	Horsfall et al[19], 2011	2616	NR	(TA)7/7, (TA)7/8	NR	NR	Exon 1	NR	NR
Sri Lanka	Premawardhena et al[34], 2003	229	115:114	(TA)7/7	NR	NR	NR	NR	NR
China	Wu et al[8], 2024	232/310	166:66	(TA)7/7, (TA)7/6, (TA)6/6	c.211G>A (p.Gly71Arg)	+/+, +/-	Exon 1	NR	NR
China	Gu et al[9], 2022	117	NR	(TA)7/7	c.211G>A (p.Gly71Arg)	+/+, +/-	Exon 1	NR	NR

M:F: Male:female ratio; CNS: Crigler-Najjar syndrome; NR: No record; +/+: Homozygous; +/-: Heterozygous; GS: Gilbert syndrome.

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Citation: Isa HM, Abdulaal FA, Busehail MY, Kamal MH, Alaswad HA, Alshaikh FY, Aljassmi AA, Hijris AJ. UGT1A1-related disorders in Bahrain: A genetic and clinical overview of Crigler-Najjar and Gilbert syndromes. World J Clin Pediatr 2026; 15(4): 121263
URL: https://www.wjgnet.com/2219-2808/full/v15/i4/121263.htm
DOI: https://dx.doi.org/10.5409/wjcp.121263

Isa HM, Abdulaal FA, Busehail MY, Kamal MH, Alaswad HA, Alshaikh FY, Aljassmi AA, Hijris AJ. UGT1A1-related disorders in Bahrain: A genetic and clinical overview of Crigler-Najjar and Gilbert syndromes. World J Clin Pediatr 2026; 15(4): 121263 [DOI: 10.5409/wjcp.121263]

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