Spectrum and classification of ATP7B variants with clinical correlation in children with Wilson disease

Ruqayah GY. Al-Obaidi; Bassam MS. Al-Musawi

doi:10.15537/smj.2025.46.2.20240997

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Table 1

- Demographic and clinical characteristics with age of onset of the enrolled children

Parameters	n	%
Gender
Male	34	61.8%
Female	21	38.2%
Parental consanguinity
Positive	47	85.5%
Negative	8	14.5%
Family history of WD or a similar condition
Positive	27	49.1%
Negative	28	50.9%
Ethnicity
Arabs	52	94.5%
Kurds	3	5.5%
Kayser-Fleischer ring
Positive	18	32.7%
Negative	37	67.3%
Clinical presentation
Hepatic	40	72.7%
Neurologic	2	3.6%
Mixed	12	21.8%
Asymptomatic	1	1.8%
Main clinical presentation
Age (years)
Hepatic	Mixed	Neurologic
N=40	N= 12	N= 2
Mean±Standard deviation	Mean±SD	Mean±SD
At presentation
9.4±3.1	8.6±3.3	8.5±7.7^*
At diagnosis
12.05±3.2	12.4±3.7	13.35±3.7 ^**

N: number, WD: Wilson disease

↵* p=0.814;
↵** p=0.742,

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Table 2

- Variants identified by targeted ATP7B gene sequencing by next-generation sequencing arranged by frequency.

#	Nucleotide change	Amino acid change	Variant effect	Variant classification by ClinVar	Region Exon/intron	Location on chromosome 13	dbSNP code	No. of alleles
1	c.3305T>C	p.Ile1102Thr	Missense	Pathogenic	15	52516629	560952220	4
2	c.956delC	p.Pro319HisfsTer44	Frameshift	Pathogenic	2	52548399	753674382	4
3	c.3741-3742 dupCA	p.Lys1248ThrfsTer83	Frameshift	Pathogenic	18	52511772	1462451206	3
4	c.3694A>C	p.Thr1232Pro	Missense	Likely pathogenic	17	52513192	568009639	3
5	c.4309A>T	p.Lys1437Ter	Stop-gain	Pathogenic	21	52508981	768833241	2
6	c.2575+1G>C	-	Splice-donor	Pathogenic	Intron 10	52524407	766149114	2
7	c.4021G>A	p.Gly1341Ser	Missense	Likely pathogenic	19	52511412	587783317	2
8	c.2336G>A	p.Trp779Ter	Stop-gain	Pathogenic	8	52532466	137853283	2
9	c.2866-2A>C	-	Splice-acceptor	Pathogenic	Intron 12	52520616	1377418826	2
10	c.2905C>T	p.Arg969Trp	Missense	Likely pathogenic	13	52520575	774028495	2
11	c.3061-12T>A	-	Intronic	Pathogenic	Intron 13	52518439	1045194246	2
12	c.2987T>C	p.Met996Thr	Missense	Pathogenic	13	52520493	770782111	2
13	c.2304dupC	p.Met769HisfsTer26	Frameshift	Pathogenic	8	52532497	193922103	2
14	c.4092-4093 delGT	p.Ser1365CysfsTer12	Frameshift	Likely pathogenic	20	52509759	747301758	2
15	c.3443T>C	p.Ile1148Thr	Missense	Pathogenic	16	52515330	60431989	2
16	c.3547-3548 delGC	p.Ala1183TyrfsTer2	Frameshift	Pathogenic	16	52515224	765139243	2
17	c.4022G>A	p.Gly1341Asp	Missense	Pathogenic	20	52509831	779494870	2
18	c.3263T>A	p.Leu1088Ter	Stop-gain	Pathogenic	15	52516671	753250853	2
19	c.2297C>G	p.Thr766Arg	Missense	Pathogenic	8	52532505	121907997	2
20	c.2827G>A	P.Gly943Ser	Missense	Pathogenic	12	52523836	28942076	2
21	c.2447+11delG	-	Intronic	Likely pathogenic	Intron 9, 11bp from exon 9	52531640	758601871	1
22	c.4051C>T	p.Gln1351Ter	Stop gain	Pathogenic	20	52509802	786204578	1
23	c.3517G>A	p.Glu1173Lys	Missense	Pathogenic	16	52515256	756029120	1
24	c.1924G>C	p.Asp642His	Missense	Pathogenic	6	52535995	72552285	1
25	c.1870-39T>C	-	Intronic	Likely pathogenic	Intron 5, 38 bp from exon 6	52536088	747432408	1
26	c.2663C>T	p.Thr888Ile	Missense	Likely pathogenic	11	52524210	935426164	1
27	c.1745-1746delTA	p.Ile582ArgfsTer25	Frameshift	Pathogenic	5	52539130	753962912	1
28	c.2332C>G	p.Arg778Gly	Missense	Pathogenic	8	52532470	137853284	1
29	c.562C>T	p.Gln188Ter	Stop-gain	Pathogenic	2	52548794	1412593296	1
30	c.2426G>A	p.Gly809Asp	Missense	VUS	9	52531673	762578415	1
31	c.1870-39T>G	-	Intronic	Not reported in ClinVar. Found in low % in ExAC	Intron 5, 39bp from exon 6	52536088	747432408	1
32	c.3556G>A	p.Gly1186Ser	Missense	Pathogenic	16	52515217	786204547	1
33	c.2002A>G	P.Met668Val	Missense	Conflicting (VUS / Likely pathogenic)	7	52534403	587783301	1
34	c.3955C>T	p.Arg1319Ter	Stop gain	Pathogenic	19	52511478	193922109	1
35	c.3472-3482delGGTTTAACCAT	p.Gly1158phefsTer	Frameshift	Pathogenic	Gross deletion	52515290	-	1
36	c.3538A>G	p.Ile1180Val	Missense	Likely pathogenic	16	52515235	1324203873	1
37	c.2730+39-2730+41delGTT	-	Intronic deletion	Likely pathogenic	Intron 11, 41bp from exon 11	52524101	751433161	1
38	c.2513delA	Lys838SerfsTer35	Frameshift	Pathogenic	10	52524469	777362050	1
39	c.314C>A	p.Ser105Ter	Stop gain	Pathogenic	2	52549042	753236073	1
40	c.3895C>T	p.Leu1299Phe	Missense	Pathogenic	18	52511620	749472361	1
41	c.2715G>C	p.Glu905Asp	Missense	VUS	11	52524158	923227127	1
42	c.3649-3654delGTTCTG	p.Val1217-Leu1218del	Inframe-deletion	Pathogenic	17	52513231	781266802	1
43	c.2804C>T	p.Thr935Met	Missense	Pathogenic	12	52523859	750019452	1
44	c.3960G>C	p.Arg1320Ser	Missense	Pathogenic	19	52511473	778732681	1
45	c.3121C>T	p.Arg1041Trp	Missense	Likely pathogenic	14	52518367	746485916	1
46	c.3836A>G	p.Asp1279Gly	Missense	Likely pathogenic	18	52511679	778914828	1
47	c.4114C>T	p.Gln1372Ter	Stop gain	Pathogenic	20	52509739	755584106	1
48	c.623C>T	p.Ala208Val	Missense	VUS but polyphen-2 possibly damaging; align-GVGD: Class C0)	2	52548733	754738204	1
49	c.3317T>A	p.Val1106Asp	Missense	Likely pathogenic	15	52516617	775541743	1
50	c.2606G>A	p.Gly869Glu	Missense	Likely pathogenic	11	52524267	775553302	1
51	c.2924C>A	p.Ser975Tyr	Missense	Pathogenic	13	52520556	778163447	1
52	c.2972C>T	p.Thr991Met	Missense	Pathogenic	13	52520508	41292782	1
53	c.2897T>G	p.Val966Gly	Missense	VUS by ACMG, SIFT: Damaging	13	52520583	761430052	1
54	c.1630C>T	p.Gln544Ter	Stop gain	Pathogenic	4	52542657	766906034	1
55	c.2576-44G>T	-	Intronic	VUS, previous analysis from invitae labs showed it is related to disease	Intron 10, 66bp from exon 10, 43bp from exon 11	52524341	746739918	1
56	c.3892G>A	p.V.1298Ile	Missense	VUS / SIFT: affect protein function	18	52511623	753044473	1
57	c.2507G>A	p.Gly836Glu	Missense	Likely pathogenic	10	52524476	773809011	1
58	c.915T>A	p.Cys305Ter	Stop gain	Pathogenic	2	52548441	398123137	1
59	c.347T>C	p.Ile116Thr	Missense	VUS Conflicting (Pathogenic by invitae)	2	52549009	199773340	1
60	c.352G>A	p.Asp118Asn	Missense	VUS by ACMG/SIFT is deleterious	2	52549004	769655497	1
61	c.1318A>G	p.Ser440Gly	Missense	VUS	3	52544853	759000301	1
62	c.1616C>T	p.pro539Leu	Missense	VUS / Likely pathogenic by ACMG	4	52542671	572122562	1
63	c.3646G>A	p.Val1216Met	Missense	Likely pathogenic	17	52513240	776280797	1
64	c.2807T>A	p.Leu936Ter	Stop gain	Pathogenic	12	52523856	776002066	1
65	c.4125-1G>A	-	Splice-acceptor	VUS / Suspicious for pathogenicity	Intron 20	52509166	1293549383	1
66	c.3182G>A	p.Gly1061Glu	Missense	Pathogenic	14	52513806	764131178	1
67	c.1924G>T	p.Asp642Tyr	Missense	Pathogenic	6	52535995	72552285	1
68	c.1934T>G	p.Met645Arg	Missense	Likely pathogenic	6	52535985	121907998	1
69	c.2530A>T	p.Lys844Ter	Stop gain	Pathogenic	10	52524453	780292767	1
70	c.2532delA	p.Val845SerfsTer28	Frameshift	Pathogenic	10	52524450	755709270	1
71	c.1708-1G>A	-	Splice acceptor	Pathogenic	Intron4	52539170	137853280	1
72	c.1543+1G>C	-	Splice donor	Pathogenic	intron3	52544627	1360279134	1
73	c.2333G>T	p.Arg778Leu	Missense	Pathogenic	8	52532469	28942074	1
74	c.2930C>T	p.Thr977Met	Missense	Pathogenic	13	52520550	72552255	1
75	c.2549C>T	p.Thr850Ile	Missense	Pathogenic	10	52524434	777629392	1
76	c.2000T>A	p.Leu667Ter	Stop gain	Likely pathogenic	7	52534405	1474837260	1

VUS: variant of uncertain significance, SIFT: Sorting Tolerant From Intolerant, #: number

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Table 3

- Variants detected in homozygous state in fifteen patients with Wilson disease.

Patients’ IDs	No. of alleles	Nucleotide change	Codon change	Variant effect	Variant classification	Presentation	MLS score after NGS
14, 23	4	c.956delC	p.Pro319HisfsTer44	Frameshift	Pathogenic	Mixed, Hepatic	10, 11
26, 50	4	c.3305T>C	p.Ile1102Thr	Missense	Pathogenic	Hepatic	8, 9
13	3	c.3741-3742dupCA^*	p.Lys1248ThrfsTer83	Frameshift	Pathogenic	Hepatic	10
51	3	c.3694A>C^{^&}	p.Thr1232Pro	Missense	Likely pathogenic	Hepatic	8
1	2	c.4309A>T	p.Lys1437Ter	Stop-gain	pathogenic	Mixed	7
4^#	2	c.2575+1G>C	-	Splice-donor	pathogenic	Hepatic	9
30^#	2	c.4021G>A	p.Gly1341Ser	Missense	Likely pathogenic	Hepatic	10
33	2	c.2336G>A	p.Trp779Ter	Stop-gain	pathogenic	Mixed	8
43^#	2	c.2866-2A>C	-	Splice acceptor	pathogenic	Hepatic	7
45	2	c.2905C>T	p.Arg969Trp	Missense	Likely pathogenic	Hepatic	8
48	2	c.3061-12T>A	-	Intronic variant	pathogenic	Hepatic	6
53	2	c.2987T>C	p.Met996Thr	Missense	pathogenic	Hepatic	7
54	2	c.2304dupC	p.Met769HisfsTer26	Frameshift	pathogenic	Mixed	10
Total: 15	32	No. of variants = 13

MLS: modified Leipzig score

↵# Those patients have one additional variant in heterozygous state, namely: (c.2663C>T, p.Thr888Ile), (c.2924C>A, p.Ser975Tyr), and (c.1934T>G, p.Met645Arg).
↵* This variant is also detected in patient no. 5 but in heterozygous state, so total no. of alleles carrying this variant were 3.
↵& : This variant is also detected in patient no. 38 but in heterozygous state, so total no of alleles carrying this variant were 3.

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Table 4

- Variants detected in compound heterozygous state in 15 patients with Wilson disease.

Pt’s ID	First variant	Effect / Classification	Second variant	Effect / Classification	Presentation	Score after NGS
2^#	c.3517G>A (p.Glu1173Lys)	Missense/pathogenic	c.4051C>T (p.Gln1351Ter)	Stop-gain / pathogenic	Hepatic	10
3	c.1924G>C (p.Asp642His)	Missense/pathogenic	c.1870-39T>C (Intronic variant)	Intronic / Likely pathogenic	Mixed	11
7	c.2332C>G (p.Arg778Gly)	Missense/pathogenic	c.562C>T (p.Gln188Ter)	Stop-gain / pathogenic	Hepatic	9
9	c.4092-4093delGT (p.Ser1365CysfsTer12)	Frameshift/pathogenic	c.3556G>A (p.Gly1186Ser)	Missense / pathogenic	Hepatic	8
11	c.3955C>T (p.Arg1319Ter)	Stop-gain / pathogenic	c.3472-3482del GGTTTAACCAT (p.Gly1158PhefsTer2)	Frameshift / pathogenic	Mixed	8
12	c.3538A>G (p.Ile1180Val)	Missense/likely pathogenic	c.2730+39-2730+41delGTT (Intronic deletion)	Intronic deletion / Likely pathogenic	Mixed	10
19	c.3649-3654del GTTCTG (p.Val1217-Leu1218del)	Inframe-deletion / pathogenic	c.2804C>T (p.Thr935Met)	Missense / pathogenic	Mixed	10
20	c.3960G>C (p.Arg1320Ser)	Missense/ pathogenic	c.3121C>T (p.Arg1041Trp)	Missense / likely pathogenic	Hepatic	7
28	c.3317T>A (p.Val1106Asp)	Missense / likely pathogenic	c.3263T>A (p.Leu1088Ter)	Stop-gain / pathogenic	Mixed	10
32	c.2972C>T (p.Thr991Met)	Missense/ pathogenic	c.2297C>G (p.Thr766Arg)	Missense / pathogenic	Hepatic	7
42	c.3182G>A (p.Gly1061Glu)	Missense/ pathogenic	c.1924G>T (p.Asp642Tyr)	Missense / pathogenic	Hepatic	8
44	c.2827G>A (p.Gly943Ser)	Missense/ pathogenic	c.2530A>T (p.Lys844Ter)	Stop-gain / Pathogenic	Hepatic	6
46	c.1708-1G>A (Splice acceptor variant)	Splice acceptor/ pathogenic	c.1543+1G>C (Splice donor variant)	Splice donor / pathogenic	Hepatic	9
47	c.3443T>C (p.Ile1148Thr)	Missense/ pathogenic	c.2333G>T (p.Arg778Leu)	Missense / pathogenic	Neuro	8
49	c.2930C>T (p.Thr977Met)	Missense/ pathogenic	c.2549C>T (p.Thr850Ile)	Missense / pathogenic	Hepatic	7

NGS: next-generation sequencing

↵# This patient had additional third variant, c.2447+11delG (intronic variant, classified as likely pathogenic).

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Table 5

- Variants characteristics detected in 12 children with 2 variants: a disease-causing variant plus a VUS or a variant with conflicting pathogenicity.

Pt’s ID	First variant (Disease causing)	Variant effect / Classification	Second variant :(Variant effect/ classification (VUS/ conflicting)	SIFT Score for the VUS ^{^*}	Predictions of functional effect with SIFT	Score after NGS
8^{^#}	c.4092-4093delGT (p.Ser1365CysfsTer12)	Frameshift/ likely pathogenic	c.2426G>A (p.Gly809Asp): missense/VUS	0.2	Tolerated	3
10	c.3443T>C (p.Ileu1148Thr)	Missense/ pathogenic	c.2002A>G (p.Met668Val): missense/ conflicting (VUS/Likely pathogenic)	0.04	Affect protein function	8
18	c.3547-3548delGC (p.Ala1183TyrfsTer2)	Frameshift/ pathogenic	c.2715G>C (p.Glu905Asp): missense/VUS	0.04	Affect protein function	9
24	c.4114C>T (p.Gln1372Ter)	Stop-gain/ pathogenic	c.623C>T (p.Ala208Val) missense/VUS	0.4	Tolerated	5
34	c.2297C>G (p.Thr766Arg)	Missense/ pathogenic	c.2897T>G (p.Val966Gly): missense/VUS	0.06	Affect protein function	6
35	c.1630C>T (p.Gln544Ter)	Stop-gain/ pathogenic	c.2576-44G>T: Intronic variant/VUS	0.05	Affect protein function	5
36	c.2507G>A (p.Gly836Glu)	Missense/ likely pathogenic	c.3892G>A (p.Val1298Ile): missense/ VUS	0.03	Affect protein function	4
37	c.915T>A (p.Cys305Ter)	Stop-gain/ pathogenic	c.347T>C (p.Ile116Thr): missense/ Conflicting (VUS/Likely pathogenic)	0.03	Affect protein function	8
38	c.3694A>C (p.Thr1232Pro)	Missense/ likely pathogenic	c.352G>A (p.Asp118Asn): missense/ conflicting (VUS/Likely benign)	0.04	Affect protein function	4
39	c.3547-3548delGC (P.Ala1183TyrfsTer2)	Frameshift/ pathogenic	c.1318A>G (p.Ser440Gly): missense/ VUS	0.02	Affect protein function	6
40	c.2827G>A (p.Gly943Ser)	Missense/ pathogenic	c.1616C>T (p.Pro539Leu): missesnse/ conflicting (VUS/Likely pathogenic)	0.02	Affect protein function	6
41	c.2807T>A (p.Leu936Ter)	Stop-gain/ pathogenic	c.4125-1G>A (Splice acceptor variant)/ VUS	0.04	Affect protein function	7

Pt’ ID: Patient’s identification, NGS: next-generation sequencing

↵* Scores less than 0.05 are considered deleterious.
↵^# This patient (ID 8) has additional heterozygous variant (13:52536088, rs747432408, c.1870-39T>G, intronic variant, has not been reported before and found in low penetrance in ExAC).

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Table 6

- Variant characteristics, clinical presentation, and MLS scores of 13 highly suspected children to have Wilson disease with a single heterozygous deleterious variant.

Patients’ IDs	Nucleotide change	Codon change	Variant effect	Variant classification	Presentation	MLS
Patients’ IDs	Nucleotide change	Codon change	Variant effect	Variant classification	Presentation	Before NGS	After NGS
5	c.3741-3742dupCA	p.Lys1248ThrfsTer83	Frameshift	Pathogenic	Hepatic	4	5
6	c.1745-1746delTA	p.Ile582ArgfsTer25	Frameshift	Pathogenic	Mixed	3	4
15	c.2513delA	p.Lys838SerfsTer35	Frameshift	Pathogenic	Hepatic	2	3
16	c.314C>A	p.Ser105Ter	Stop-gain	Pathogenic	Hepatic	5	6
17	c.3895C>T	p.Leu1299phe	Missense	Pathogenic	Hepatic	4	5
22	c.3836A>G	p.Asp1279Gly	Missense	Pathogenic/likely pathogenic	Hepatic	2	3
25	c.4022G>A	p.Gly1341Asp	Missense	Pathogenic	Mixed	3	4
27	c.3263T>A	p.Leu1088Ter	Stop-gain	Pathogenic	Neuropsychiatric	2	3
29	c.2606G>A	p.Gly869Glu	Missense	VUS/Likely pathogenic	Hepatic	3	4
52	c.2000T>A	p.Leu667Ter	Stop-gain	Pathogenic/likely pathogenic	Hepatic	4	5
55	c.3646G>A	p.Val1216Met	Missense	Pathogenic/Likely pathogenic	Asymptomatic	3	4
56	c.2532delA	p.Val845SerfsTer28	Frameshift	Pathogenic	Hepatic	2	3
57	c.4022G>A	p.Gly1341Asp	Missense	Pathogenic	Hepatic	2	3