Background
Materials and methods
Literature search strategy
Duplicate exclusion
Eligibility assessment
Data extraction
Annotation and prediction of the pathogenicity of variants
Nomenclature
Statistical analysis
Results
Literature search and inclusion of cases
HJV-HH Cases with biallelic mutations | HJV-HH Cases with a single mutation |
P
| |||||
---|---|---|---|---|---|---|---|
All | Probands | Non-probands | All | Probands | Non-probands | ||
N | 117 | 97 | 20 | 15 | 9 | 6 | |
Male, n (%) | 61 (52.14) | 52 (53.61) | 9 (45.00) | 10 (66.67) | 5 (55.56) | 5 (83.33) | 9.11 × 10-1C |
Ethnicities Caucasian/East Asian/African/ND, (%) | 98/18/1/0 (83.76/15.38/8.55/0.00) | 83/13/1/0 (85.57/13.40/1.03/0.00) | 15/5/0/0 (75.00/25.00/0.00/0.00) | 3/9/0/3 (20.00/60.00/0.00/20.00) | 2/4/0/3 (22.22/44.44/0.00/33.33) | 1/5/0/0 (16.67/83.33/0.00/0.00) |
6.71 × 10
-3
F
a
|
Homozygotes, n (%) | 89 (76.07) | 73 (75.26) | 16 (80.00) | — | — | — | — |
Age at diagnosis (year) | 25.00 (20.00, 32.00) | 26.00 (21.00, 32.00) | 21.00 (16.00, 28.50) | 53.00 (36.00, 65.00) | 58.00 (36.00, 62.00) | 48.00 (46.00, 70.00) |
8.02 × 10
-4
W
|
Age at presentation (year) | 21.50 (18.00, 28.00) | 22.50 (19.50, 27.50) | 16.50 (13.00, 32.00) | — | — | — | — |
Disease onset before 30 years, n (%) | 88 (75.21) | 72 (74.23) | 16 (80.00) | 4 (26.67) | 3 (33.33) | 1 (16.67) |
1.75 × 10
-2
F
|
Serum parameters at presentation | |||||||
Serum ferritin (ng/ml) | 3541.80 (2270.00, 5293.00) | 3700.00 (2329.00, 5520.00) | 1971.50 (1117.50, 4314.00) | 444.00 (356.00, 1402.00) | 784.50 (388.50, 1512.50) | 382.50 (266.00, 554.00) |
2.70 × 10
-5
W
|
Transferrin saturation (%) | 94.00 (90.00, 100.00) | 95.00 (89.00, 100.00) | 92.00 (90.00, 97.00) | 49.00 (40.00, 68.00) | 64.00 (47.00, 83.00) | 40.00 (34.00, 46.00) |
1.03 × 10
-4
W
|
Complications | |||||||
Cardiomyopathy, n (%) | 40 (34.19) | 36 (37.11) | 4 (20.00) | 1 (6.67) | 1 (11.11) | 0 (0.00) | 1.57 × 10-1F |
Skin hyperpigmentation, n (%) | 48 (41.03) | 40 (41.24) | 8 (40.00) | 2 (13.33) | 1 (11.11) | 1 (16.67) | 1.49 × 10-1F |
Arthropathy, n (%) | 32 (27.35) | 27 (27.84) | 5 (25.00) | 1 (6.67) | 1 (11.11) | 0 (0.00) | 4.40 × 10-1F |
Endocrine abnormality | |||||||
Hypogonadism, n (%) | 70 (59.83) | 63 (64.95) | 7 (35.00) | 2 (13.33) | 1 (11.11) | 1 (16.67) |
2.95 × 10
-3
F
|
Glucose intolerance, n (%) | 36 (30.77) | 33 (34.02) | 3 (15.00) | 2 (13.33) | 1 (11.11) | 1 (16.67) | 2.66 × 10-1F |
Osteopathy, n (%) | 11 (9.40) | 7 (7.22) | 4 (20.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 1.00 × 10-1F |
Thyroid abnormality, n (%) | 9 (7.69) | 7 (7.22) | 2 (10.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 1.00 × 10-1F |
Liver disease | |||||||
Abnormal liver function test, n (%) | 39 (33.33) | 35 (36.08) | 4 (20.00) | 4 (26.67) | 3 (33.33) | 1 (16.67) | 1.00 × 10-1F |
Liver iron deposition, n (%) | 74 (63.25) | 67 (69.07) | 7 (35.00) | 4 (26.67) | 4 (44.44) | 0 (0.00) | 1.53 × 10-1F |
Liver fibrosis, n (%) | 43 (36.75) | 39 (40.21) | 4 (20.00) | 1 (6.67) | 1 (11.11) | 0 (0.00) | 1.49 × 10-1F |
Liver cirrhosis, n (%) | 28 (23.93) | 26 (26.80) | 2 (10.00) | 1 (6.67) | 1 (11.11) | 0 (0.00) | 4.43 × 10-1F |
Liver biopsy, n (%) | 62 (52.99) | 56 (57.73) | 6 (30.00) | 3 (20.00) | 3 (33.33) | 0 (0.00) | 1.81 × 10-1F |
Therapy Phlebotomy/Chelating agent/Phlebotomy & Chelating agent/ND, n (%) | 60/3/7/47 (51.28/2.56/5.98/40.17) | 46/3/7/41 (47.42/3.09/7.22/42.27) | 14/0/0/6 (70.00/0.00/0.00/30.00) | 3/0/0/12 (20.00/0.00/0.00/80.00) | 2/0/0/7 (22.22/0.00/0.00/77.78) | 1/0/0/5 (16.67/0.00/0.00/83.33) | — |
Phenotypic spectrum of the biallelic HJV mutation cases
Probands | Non-probands | |||||
---|---|---|---|---|---|---|
Onset age ≤30 years | Onset age >30 years |
P
| Onset age ≤30 years | Onset age >30 years |
P
| |
N | 72 | 25 | 16 | 4 | ||
Male, n (%) | 37 (51.39) | 15 (60.00) | 4.57 × 10-1C | 8 (50.00) | 1 (25.00) | 5.91 × 10-1F |
Homozygotes, n (%) | 54 (75.00) | 19 (76.00) | 9.21 × 10-1C | 12 (75.00) | 4 (100.00) | 5.38 × 10-1F |
Age at diagnosis (year) | 24.00 (19.50, 27.50) | 39.00 (32.00, 49.00) |
1.53 × 10
-12
W
| 19.00 (16.00, 22.50) | 45.50 (36.00, 53.00) |
2.86 × 10
-3
W
|
Age at presentation (year) | 21.00 (18.00, 25.00) | 33.50 (32.00, 39.00) |
7.10 × 10
-7
W
| 15.00 (12.00, 17.00) | 34.00 (32.00, 49.00) |
2.18 × 10
-2
W
|
Serum parameters at presentation | ||||||
Serum ferritin (ng/ml) | 3520.90 (2291.50, 5782.50) | 3987.00 (2680.00, 4959.00) | 6.16 × 10-1W | 1971.50 (1117.50, 3498.50) | 2753.50 (869.50, 6981.50) | 9.52 × 10-1W |
Transferrin saturation (%) | 95.50 (89.00, 100.00) | 93.50 (89.00, 99.50) | 4.73 × 10-1W | 92.00 (90.00, 98.00) | 92.00 (75.00, 94.90) | 5.46 × 10-1W |
Complications | ||||||
Cardiomyopathy, n (%) | 29 (40.28) | 7 (28.00) | 2.74 × 10-1C | 3 (18.75) | 1 (25.00) | 1.00 × 10-0F |
Skin hyperpigmentation, n (%) | 29 (40.28) | 11 (44.00) | 7.45 × 10-1C | 6 (37.50) | 2 (50.00) | 1.00 × 10-0F |
Arthropathy, n (%) | 18 (25.00) | 9 (36.00) | 2.90 × 10-1C | 4 (25.00) | 1 (25.00) | 1.00 × 10-0F |
Endocrine abnormality | ||||||
Hypogonadism, n (%) | 54 (75.00) | 9 (36.00) |
4.30 × 10
-4
C
| 6 (37.50) | 1 (25.00) | 1.00 × 10-0F |
Glucose intolerance, n (%) | 21 (29.17) | 12 (48.00) | 8.68 × 10-2C | 2 (12.50) | 1 (25.00) | 5.09 × 10-1F |
Osteopathy, n (%) | 6 (8.33) | 1 (4.00) | 6.73 × 10-1F | 4 (25.00) | 0 (0.00) | 5.38 × 10-1F |
Thyroid abnormality, n (%) | 4 (5.56) | 3 (12.00) | 3.69 × 10-1F | 3 (18.75) | 1 (25.00) | 1.00 × 10-0F |
Liver disease | ||||||
Abnormal liver function test, n (%) | 23 (31.94) | 12 (48.00) | 1.50 × 10-1C | 3 (18.75) | 1 (25.00) | 1.00 × 10-0F |
Liver iron deposition, n (%) | 43 (59.72) | 24 (96.00) |
7.22 × 10
-4
C
| 6 (37.50) | 1 (25.00) | 1.00 × 10-0F |
Liver fibrosis, n (%) | 31 (43.06) | 8 (32.00) | 3.31 × 10-1C | 3 (18.75) | 1 (25.00) | 1.00 × 10-0F |
Liver cirrhosis, n (%) | 20 (27.78) | 6 (24.00) | 7.13 × 10-1C | 1 (6.25) | 1 (25.00) | 3.68 × 10-1F |
Liver biopsy, n (%) | 41 (56.94) | 15 (60.00) | 7.90 × 10-1C | 5 (31.25) | 1 (25.00) | 1.00 × 10-0F |
Therapy Phlebotomy/Chelating agent/Phlebotomy & Chelating agent/ND, n (%) | 28/2/6/36 (38.89/2.78/8.33/50.00) | 18/1/1/5 (72.00/4.00/4.00/20.00) | — | 11/0/0/5 (68.75/0.00/0.00/31.25) | 3/0/0/1 (75.00/0.00/0.00/25.00) | — |
Comparisons of phenotypes between Caucasian and East Asian probands with biallelic HJV mutation
Probands | Non-probands | |||||
---|---|---|---|---|---|---|
Caucasians | East Asians |
P
| Caucasians | East Asians |
P
| |
N | 83 | 13 | 15 | 5 | ||
Male, n (%) | 40 (48.19) | 11 (84.62) |
1.72 × 10
-2
F
| 6 (40.00) | 3 (60.00) | 6.17 × 10-1F |
Homozygotes, n (%) | 64 (77.11) | 8 (61.54) | 3.00 × 10-1F | 12 (80.00) | 4 (80.00) | 1.00 × 10-1F |
Age at diagnosis (year) | 26.00 (21.00, 32.00) | 26.00 ( 19.00, 37.00) | 6.72 × 10-1W | 20.00 ( 16.00, 24.00) | 27.00 ( 22.00, 51.00) | 8.03 × 10-2W |
Age at presentation (year) | 22.50 (20.00, 27.00) | 21.50 ( 14.00, 48.00) | 8.73 × 10-1W | — | — | — |
Disease onset before 30 years, n (%) | 63 (75.90) | 8 (61.54) | 3.13 × 10-1F | 13 (86.67) | 3 (60.00) | 2.49 × 10-1F |
Serum parameters at presentation | ||||||
Serum ferritin (ng/ml) | 3553.00 (2329.00, 5293.00) | 4974.00 (2337.00,6678.00) | 2.21 × 10-1W | 1648.00 (1117.50, 3498.50) | 3389.00 (1505.00,5273.50) | 6.71 × 10-1W |
Transferrin saturation (%) | 95.00 (88.00, 100.00) | 94.40 ( 92.05, 97.55) | 9.80 × 10-1W | 92.00 (80.00, 98.00) | 93.70 ( 91.00, 95.60) | 8.01 × 10-1W |
Complications | ||||||
Cardiomyopathy, n (%) | 29 (34.94) | 7 (53.85) | 2.26 × 10-1F | 3 (20.00) | 1 (20.00) | 1.00 × 10-1F |
Skin hyperpigmentation, n (%) | 35 (42.17) | 5 (38.46) | 1.00 × 10-0F | 6 (40.00) | 2 (40.00) | 1.00 × 10-1F |
Arthropathy, n (%) | 27 (32.53) | 0 (0.00) |
1.69 × 10
-2
F
| 5 (33.33) | 0 (0.00) | 2.66 × 10-1F |
Endocrine abnormality | ||||||
Hypogonadism, n (%) | 59 (71.08) | 4 (30.77) |
9.30 × 10
-3
F
| 6 (40.00) | 1 (20.00) | 6.13 × 10-1F |
Glucose intolerance, n (%) | 26 (31.33) | 7 (53.85) | 1.27 × 10-1F | 1 (6.67) | 2 (40.00) | 1.40 × 10-1F |
Osteopathy, n (%) | 7 (8.43) | 0 (0.00) | 5.88 × 10-1F | 4 (26.67) | 0 (0.00) | 5.30 × 10-1F |
Thyroid abnormality, n (%) | 7 (8.43) | 0 (0.00) | 5.88 × 10-1F | 2 (13.33) | 0 (0.00) | 1.00 × 10-1F |
Liver disease | ||||||
Abnormal liver function test, n (%) | 28 (33.73) | 7 (53.85) | 2.17 × 10-1F | 2 (13.33) | 2 (40.00) | 2.49 × 10-1F |
Liver iron deposition, n (%) | 55 (66.27) | 11 (84.62) | 3.34 × 10-1F | 5 (33.33) | 2 (40.00) | 1.00 × 10-1F |
Liver fibrosis, n (%) | 36 (43.37) | 3 (23.08) | 2.29 × 10-1F | 4 (26.67) | 0 (0.00) | 5.30 × 10-1F |
Liver cirrhosis, n (%) | 22 (26.51) | 4 (30.77) | 7.45 × 10-1F | 1 (6.67) | 1 (20.00) | 4.47 × 10-1F |
Liver biopsy, n (%) | 48 (57.83) | 8 (61.54) | 1.00 × 10-1F | 4 (26.67) | 2 (40.00) | 6.13 × 10-1F |
Therapy Phlebotomy/Chelating agent/Phlebotomy & Chelating agent/ND, n (%) | 41/2/6/34 (49.40/2.41/7.23/40.96) | 5/0/1/7 (38.46/0.00/7.69/53.85) | — | 12/0/0/3 (80.00/0.00/0.00/20.00) | 2/0/0/3 (40.00/0.00/0.00/60.00) | — |
Phenotypic spectrum of the monoallelic HJV mutation cases
Mutation profiles in different ethnicities
Nucleotide change | Amino acid change | Coordinates (GRCh37/hg19) | RSID | Allele frequency reported | Bioinformatics prediction of missense variant | Number of reported probands | Family of origin | Ethnicity reported | Reference | Included and excluded cases in the present study ref | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1000G | ESP | ExAC | GnomAD | PolyPhen-2 (HumDiv) | PolyPhen-2 (HumVar) | Provean | |||||||||
c.9G>C | p.Glu3Asp (p.E3D) | chr1:145414790 | rs12025510 | 3.00×10-3 | NA | 1.25×10-3 | 1.19×10-3 | Benign | Benign | Neutral | 5 | China | East Asian | 9 | Included: Heterozygote: 5 [9] |
c.18G>C | p.Gln6His (p.Q6H) | chr1:145414799 | rs376970642 | NA | 7.70×10-5 | 2.47×10-5 | 2.00×10-5 | Benign | Benign | Neutral | 6 | China | East Asian | 9,10,11,29 | |
c.55A>G | p.Thr19Ala (p.T19A) | chr1:145414836 | rs781981862 | NA | NA | 8.24×10-6 | 8.16×10-6 | Benign | Benign | Neutral | 1 | China | East Asian | 15 | Excluded: Heterozygote: 1 [15] |
c.81delG | p.Leu28SerfsTer24 (p.L28fs) | chr1:145414862 | NA | NA | NA | NA | NA | — | — | — | 1 | England/Ireland | Caucasian | 30 | Included: Homozygote: 1 [30] |
c.122G>C | p.Arg41Pro (p.R41P) | chr1:145415303 | rs781785800 | NA | NA | 8.30×10-6 | 4.08×10-6 | Probably damaging | Probably damaging | Deleterious | 1 | France | Caucasian | 26 | Included: Compound heterozygote: 1 [26] |
c.138C>A | p.Tyr46Ter (p.Y46*) | chr1:145415319 | NA | NA | NA | NA | NA | — | — | — | 1 | China | East Asian | 31 | Included: Homozygote: 1 [31] |
c.160A>T | p.Arg54Ter (p.R54*) | chr1:145415341 | rs121434375 | NA | NA | NA | NA | — | — | — | 1 | African American | African American | 17 | Excluded: Heterozygote: 1 [17] |
c.196G>T | p.Gly66Ter (p.G66*) | chr1:145415377 | rs1469129426 | NA | NA | NA | NA | — | — | — | 2 | Czech, Romania: | Caucasian | 32,33 | |
c.204_205insGGA | p.Gly69dup (p.G69dup) | chr1:145415386_145415387insGGA | NA | NA | NA | NA | NA | — | — | — | 1 | United States (African American) | African American | 34 | Excluded: Heterozygote: 1 [34] |
c.208C>T | p.Arg70Trp (p.R70W) | chr1:145415389 | rs377513689 | NA | 1.54×10-4 | 5.06×10-5 | 3.31×10-5 | Probably damaging | Possibly damaging | Neutral | 1 | France | Caucasian | 35 | Excluded: Heterozygote: 1 [35] |
c.220delG | p.Val74TrpfsTer40 (p.V74fs) | chr1:145415401 | NA | NA | NA | NA | NA | — | — | — | 1 | England | Caucasian | 18 | Included: Compound heterozygote: 1 [18] |
c.238T>C | p.Cys80Arg (p.C80R) | chr1:145415419 | rs28940586 | NA | NA | 8.50×10-6 | 4.16×10-6 | Probably damaging | Probably damaging | Deleterious | 2 | Southeast United States, Australia | Caucasian | 28,36 | |
c.239G>A | p.Cys80Try (p.C80Y) | chr1: 145415420 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 1 | Bangladesh/United Kingdom | Caucasian | 37 | Included: Compound heterozygote: 1 [37] |
c.253T>C | p.Ser85Pro (p.S85P) | chr1:145415434 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 1 | Italy | Caucasian | 18 | Included: Homozygote: 1 [18] |
c.265T>C | p.Cys89Arg (p.C89R) | chr1:145415446 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 1 | Western Iran | Caucasian | 38 | Included: Homozygote: 1 [38] |
c.295G>A | p.Gly99Arg (p.G99R) | chr1:145415476 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 3 | Pakistan, Albania | Caucasian | 18,37 | |
c.296G>T | p.Gly99Val (p.G99V) | chr1:145415477 | rs1451187897 | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 1 | Greece | Caucasian | 5 | Included: Homozygote: 1 [5] |
c.302T>C | p.Leu101Pro (p.L101P) | chr1: 145415483 | rs74315327 | NA | NA | 8.65×10-6 | 8.41×10-6 | Probably damaging | Probably damaging | Deleterious | 7 | Southeast United, Albania, France | Caucasian | 18,26,27,36 | Excluded: Heterozygote: 2 [27] |
c.306delC | p.Phe103SerfsTer11 (p.F103fs) | chr1:145415487 | NA | NA | NA | NA | NA | — | — | — | 1 | Italy | Caucasian | 7 | Included: Heterozygote: 1 [7] |
c.309C>G | p.Phe103Leu (p.F103L) | chr1:145415490 | NA | NA | NA | NA | NA | Possibly damaging | Benign | Deleterious | 1 | China | East Asian | 9 | Included: Homozygote: 1 [9] |
c.311A>G | p.His104Arg (p.H104R) | chr1:145415492 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 1 | China | East Asian | 9 | Included: Compound heterozygote: 1 [9] |
c.314C>T | p.Ser105Leu (p.S105L) | chr1:145415495 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 1 | France | Caucasian | 27 | Excluded: Heterozygote: 1 [27] |
c.346C>T | p.Gln116Ter (p.Q116*) | chr1:145415527 | NA | NA | NA | NA | NA | — | — | — | 1 | Ireland | Caucasian | 39 | Included: Compound heterozygote: 1 [39] |
c.356G>T | p.Cys119Phe (p.C119F) | chr1:145415537 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 1 | Germany | Caucasian | 40 | Included: Homozygote: 1 [40] |
c.391_403del | p.Arg131PhefsTer111 (p.R131fs) | chr1:145415572_145415584del | rs1486905702 | NA | NA | NA | NA | — | — | — | 1 | Italy | Caucasian | 18 | Included: Homozygote: 1 [18] |
c.404T>G | p.Leu135Arg (p.L135R) | chr1:145415585 | rs782182681 | NA | NA | 2.75×10-5 | 1.29×10-5 | Benign | Benign | Neutral | 1 | Spanish | Caucasian | 25 | Excluded: Heterozygote: 1 [25] |
c.445delG | p.Asp149ThrfsTer97 (p.D149fs) | chr1:145415626 | NA | NA | NA | NA | NA | — | — | — | 4 | Italy | Caucasian | 8,18 | Excluded: Homozygote: 1 [18] |
c.494T>A | p.Leu165Ter (p.L165*) | chr1:145415675 | rs782431871. | NA | NA | 8.36×10-6 | 8.32×10-6 | — | — | — | 2 | Netherland | Caucasian | 16,21 | |
c.497A>G | p.His166Arg (p.H166R) | Chr1:145415678 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 1 | Arab | Caucasian | 41 | Included: Homozygote: 1 [41] |
c.503C>A | p.Ala168Asp (p.A168D) | chr1:145415684 | rs782125244 | NA | NA | NA | NA | Probably damaging | Probably damaging | Neutral | 1 | Australia/England | Caucasian | 18 | Included: Homozygote: 1 [18] |
c.509T>C | p.Phe170Ser (p.F170S) | chr1:145415690 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 2 | Italy | Caucasian | 18 | Included: Homozygote: 2 [18] |
c.512G>T | p.Gly171Val (p.G171V) | chr1:145415693 | rs782077224 | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | NA | Not mentioned | Not mentioned | 42 | NA [42] |
c.516C>G | p.Asp172Glu (p.D172E) | chr1:145415697 | rs782708481 | NA | NA | 8.35×10-6 | 4.16×10-6 | Probably damaging | Probably damaging | Deleterious | 1 | Italy | Caucasian | 18 | Included: Compound heterozygote: 1 [18] |
c.515_516insC | p.His174ProfsTer23 (p.H174fs) | chr1:145415696_145415697insC | NA | NA | NA | NA | NA | — | — | — | 1 | Japan | East Asian | 43,44 | |
c.526C>T | p.Arg176Cys (p.R176C) | chr1:145415707 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 3 | France | Caucasian | 19,22,26,45 | |
c.539A>G | p.His180Arg (p.H180R) | chr1:145415720 | rs1395419937 | NA | NA | NA | 2.07×10-5 | Benign | Benign | Neutral | 1 | France | Caucasian | 26 | Included: Compound heterozygote: 1 [26] |
c.573G>T | p.Trp191Cys (p.W191C) | chr1:145415754 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 1 | Italy | Caucasian | 18 | Included: Homozygote: 1 [18] |
c.575C>T | p.Pro192Leu (p.P192L) | chr1:145415756 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 1 | Pakistan | Caucasian | 46 | Included: Homozygote: 1 [46] |
c.581T>C | p.Leu194Pro (p.L194P) | chr1:145415762 | rs782682271 | NA | NA | 8.34×10-6 | 8.26×10-6 | Probably damaging | Probably damaging | Deleterious | 1 | Pakistan | Caucasian | 46 | Included: Homozygote: 1 [46] |
c.588T>G | p.Asn196Lys (p.N196K) | chr1:145415769 | rs1020058448 | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 1 | Italy | Caucasian | 8 | Excluded: Heterozygote: 1 [8] |
c.615C>G | p.Ser205Arg (p.S205R) | chr1:145415796 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Neutral | 1 | Italy | Caucasian | 18 | Included: Compound heterozygote: 1 [18] |
c.665T>A | p.Ile222Asn (p.I222N) | chr1:145416320 | rs74315325 | NA | 7.70×10-5 | 8.24×10-6 | 2.44×10-5 | Probably damaging | Probably damaging | Deleterious | 2 | Southeast United States, Canada | Caucasian | 5,36 | Included: Compound heterozygote: 1 [36] Excluded: Compound heterozygote: 1 [5] |
c.700_702delAAG | p.Lys234del (p.K234del) | chr1:145416355_145416357delAAG | NA | NA | NA | NA | NA | — | — | — | 1 | Europe | Caucasian | 47 | Included: Homozygote: 1 [47] |
c.739T>A | p.Phe247Ile (p.F247I) | chr1:145416394 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 1 | Turkey | Caucasian | 16 | Included: Homozygote: 1 [16] |
c.745G>C | p.Asp249His (p.D249H) | chr1:145416400 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 2 | Japan | East Asian | 43,48-50 | |
c.749G>T | p.Gly250Val (p.G250V) | chr1:145416404 | rs863224819 | NA | NA | NA | 3.23×10-5 | Probably damaging | Probably damaging | Deleterious | 1 | Italy | Caucasian | 18 | Included: Compound heterozygote: 1 [18] |
c.791C>T | p.Ser264Leu (p.S264L) | chr1:145416446 | rs782576713 | NA | NA | 1.65×10-5 | 2.03×10-5 | Possibly damaging | Benign | Neutral | 1 | Spanish | Caucasian | 23 | Excluded: Heterozygote: 1 [23] |
c.806dupA | p.Asn269LysfsTer43 (p.N269fs) | chr1:145416461dupA | NA | NA | NA | NA | NA | — | — | — | 1 | England | Caucasian | 18 | Included: Compound heterozygote: 1 [18] |
c.820G>A | p.Val274Met (p.V274M) | chr1:145416475 | rs187777957 | 5.99×10-4 | NA | 9.88×10-5 | 8.53×10-5 | Probably damaging | Probably damaging | Deleterious | 1 | China | East Asian | 9 | Included: Compound heterozygote: 1 [9] |
c.842T>C | p.Ile281Thr (p.I281T) | chr1:145416497 | rs74315326 | NA | NA | NA | 8.12×10-6 | Probably damaging | Probably damaging | Deleterious | 3 | Greece, China | Caucasian, East Asian | 5,9,10 | |
c.860T>G | p.Ile287Ser (p.I287S) | chr1:145416515 | NA | NA | NA | NA | NA | Possibly damaging | Possibly damaging | Deleterious | 1 | China | East Asian | 31 | Included: Homozygote: 1 [31] |
c.862C>T | p.Arg288Trp (p.R288W) | chr1:145416517 | rs782493762 | NA | NA | 1.65×10-5 | 1.62×10-5 | Probably damaging | Probably damaging | Deleterious | 2 | France | Caucasian | 18,26,51 | |
c.895A>G | p.Lys299Glu (p.K299E) | chr1:145416550 | NA | NA | NA | NA | NA | Benign | Benign | Neutral | 1 | France | Caucasian | 26 | Included: Compound heterozygote: 1 [26] |
c.904G>A | p.Glu302Lys (p.E302K) | chr1:145416559 | rs143496559 | 3.99×10-4 | 3.08×10-4 | 2.64×10-4 | 2.72×10-4 | Probably damaging | Possibly damaging | Deleterious | 4 | Brazil, France | Caucasian | 12,27 | Included: Heterozygote: 2 [12] Excluded: Heterozygote: 2 [27] |
c.929C>G | p.Ala310Gly (p.A310G) | chr1:145416584 | rs7540883 | 2.66×10-2 | 2.52×10-2 | 6.97×10-3 | 5.43×10-3 | Probably damaging | Possibly damaging | Neutral | 22 | Brazil, United States (African American) | Caucasian, African American | 12,34 | Included: Heterozygote: 1 [12] Excluded: Heterozygote: 21 [34] |
c.934C>T | p.Gln312Ter (p.Q312*) | chr1:145416589 | NA | NA | NA | NA | NA | — | — | — | 3 | Japan, China | East Asian | 9,48,49,52 | Excluded: Homozygote: 1 [9] |
c.950G>C | p.Cys317Ser (p.C317S) | chr1:145416605 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 1 | Italy | Caucasian | 53 | Included: Homozygote: 1 [53] |
c.959G>T | p.Gly320Val (p.G320V) | chr1:145416614 | rs74315323 | NA | 3.08×10-4 | 1.73×10-4 | 1.58×10-4 | Probably damaging | Probably damaging | Deleterious | 45 | Bangladesh/United Kingdom, Ireland, Netherland, Southeast United States, United States, Slovakia, Kosovo, Germany, Denmark, Belgium, Canada, Hungary, Australia, Croatia, Brazil, Romania, Greece, Serbia, Italy, France, India | Caucasian | 5,12,16,18-20,22,24,26-28,34,36,37,39,40,46,54-65 | |
c.960dupG | p.Cys321ValfsTer21 (p.C321fs) | chr1:145416615_145416616insG | NA | NA | NA | NA | NA | — | — | — | 2 | Italy | Caucasian | 7,18 | Included: Compound heterozygote: 1 [18] Excluded: Heterozygote: 1 [7] |
c.963C>G | p.Cys321Trp (p.C321W) | chr1:145416618 | rs121434374 | NA | NA | 1.65×10-5 | 1.22×10-5 | Probably damaging | Probably damaging | Deleterious | 1 | United States | Caucasian | 34 | Included: Compound heterozygote: 1 [34] |
c.962_963delGCinsAA | p.Cys321Ter (p.C321*) | chr1:145416617_145416618delinsAA | NA | NA | NA | 8.24×10-6 | NA | — | — | — | 6 | China | East Asian | 9-11,29 | |
c.976C>T | p.Arg326Ter (p.R326*) | chr1:145416631 | rs74315324 | NA | 7.70×10-5 | 1.65×10-5 | 1.22×10-5 | — | — | — | 2 | Australia, Greece | Caucasian | 5,28 | Included: Compound heterozygote: 1 [28] Excluded: Compound heterozygote: 1 [5] |
c.982_985delTCTC | p.Ser328AspfsTer10 (p.S328fs) | chr1: 145416637_145416640delTCTC | rs786205063 | NA | NA | NA | NA | — | — | — | 1 | Slovakia | Caucasian | 40 | Included: Compound heterozygote: 1 [40] |
c.1004G>A | p.Arg335Gln (p.R335Q) | chr1:145416659 | rs377109351 | NA | 1.54×10-4 | 7.41×10-5 | 5.69×10-5 | Possibly damaging | Benign | Neutral | 2 | France | Caucasian | 27 | Excluded: Heterozygote: 2 [27] |
c.1006G>T | p.Gly336Ter (p.G336*) | chr1:145416661 | NA | NA | NA | NA | NA | — | — | — | 4 | India | Caucasian | 66 | Included: Homozygote: 4 [66] |
c.1026delT | p.Ala343ProfsTer24 (p.A343fs) | chr1:145416681delT | NA | NA | NA | NA | NA | — | — | — | 1 | Sri Lanka | Caucasian | 37 | Included: Homozygote: 1 [37] |
c.1080delC | p.Cys361ValfsTer6 (p.C361fs) | chr1:145416735delC | NA | NA | NA | NA | NA | — | — | — | 1 | Greece | Caucasian | 5 | Included: Homozygote: 1 [5] |
c.1081T>C | p.Cys361Arg (p.C361R) | chr1:145416736 | NA | NA | NA | NA | NA | Probably damaging | Probably damaging | Deleterious | 1 | France | Caucasian | 26 | Excluded: Compound heterozygote: 1 [26] |
c.1097T>A | p.Leu366Ter (p.L366*) | chr1:145416752 | rs1205047449 | NA | NA | NA | NA | — | — | — | 1 | Canada | Caucasian | 20 | Included: Homozygote: 1 [20] |
c.1114A>G | p.Asn372Asp (p.N372D) | chr1:145416769 | rs782156457 | NA | NA | 8.24×10-6 | 1.22×10-5 | Possibly damaging | Benign | Deleterious | 1 | France | Caucasian | 27 | Excluded: Heterozygote: 1 [27] |
c.1151C>T | p.Ala384Val (p.A384V) | chr1:145416806 | NA | NA | NA | NA | NA | Possibly damaging | Possibly damaging | Neutral | 1 | France | Caucasian | 26 | Included: Compound heterozygote: 1 [26] |
c.1153C>T | p.Arg385Ter (p.R385*) | chr1:145416808 | rs782803011 | NA | NA | 8.24×10-6 | 2.03×10-5 | — | — | — | 3 | Italy, North Africa | Caucasian, North African | 18,26 | |
c.-89-4dupT | — | chr1:145414649 | NA | NA | NA | NA | NA | — | — | — | 1 | France | Caucasian | 19 | Excluded: Heterozygote: 1 [19] |
c.-36G>A | — | chr1:145414746 | NA | NA | NA | NA | NA | — | — | — | 2 | India | Caucasian | 66 | Included: Compound heterozygote: 2 [66] |
c.-1624G>A | — | chr1:145413158 | NA | NA | NA | NA | NA | — | — | — | 2 | India | Caucasian | 66 | Included: Compound heterozygote: 2 [66] |
Gene deletion | — | — | — | NA | NA | NA | NA | — | — | — | 1 | Canada | Caucasian | 20 | Included: Heterozygote: 1 [20] |
Genotype–phenotype correlation in HJV-variant homozygotes
Exon 2-3 | Exon 4 |
P
| |
---|---|---|---|
N | 23 | 50 | |
Male, n (%) | 14 (60.87%) | 29 (58.00%) | 8.17 × 10-1C |
Ethnicities Caucasian/East Asian/African, n (%) | 20/3/0 (86.96/13.04/0.00) | 44/5/1 (88.00/10.00/2.00) | 7.04 × 10-1Fa |
Age at diagnosis (year) | 23.00 (20.00, 26.00) | 28.00 (24.00, 37.00) |
6.96 × 10
-3
W
|
Age at presentation (year) | 22.50 (20.00, 25.50) | 25.00 (20.00, 32.00) | 1.71 × 10-1W |
Disease onset before 30 years, n (%) | 21 (91.30%) | 33 (66.00%) |
2.40 × 10
-2
C
|
Serum parameters at presentation | |||
Serum ferritin (ng/ml) | 3065.00 (2000.00, 4485.00) | 4018.50 (2500.00, 6008.50) | 1.23 × 10-1W |
Transferrin saturation (%) | 95.00 (90.00, 100.00) | 96.00 (91.00, 100.00) | 5.62 × 10-1W |
Complications | |||
Cardiomyopathy, n (%) | 7 (30.43%) | 21 (42.00%) | 3.45 × 10-1C |
Skin hyperpigmentation, n (%) | 5 (21.74%) | 25 (50.00%) |
3.92 × 10
-2
F
|
Arthropathy, n (%) | 4 (17.39%) | 14 (28.00%) | 3.94 × 10-1F |
Endocrine abnormality | |||
Hypogonadism, n (%) | 18 (78.26%) | 31 (62.00%) | 1.70 × 10-1C |
Glucose intolerance, n (%) | 6 (26.09%) | 16 (32.00%) | 6.09 × 10-1C |
Osteopathy, n (%) | 1 (4.35%) | 4 (8.00%) | 1.00 × 10-1F |
Thyroid abnormality, n (%) | 0 (0.00%) | 3 (6.00%) | 5.47 × 10-1F |
Liver disease | |||
Abnormal liver function test, n (%) | 8 (34.78%) | 19 (38.00%) | 7.91 × 10-1C |
Liver iron deposition, n (%) | 15 (65.22%) | 35 (70.00%) | 6.83 × 10-1C |
Liver fibrosis, n (%) | 12 (52.17%) | 20 (40.00%) | 3.30 × 10-1C |
Liver cirrhosis, n (%) | 7 (30.43%) | 13 (26.00%)) | 6.93 × 10-1C |
Liver biopsy, n (%) | 17 (73.91%) | 25 (50.00%) | 5.48 × 10-2C |
Therapy Phlebotomy/Chelating agent/Phlebotomy & Chelating agent/ND, n (%) | 6/0/2/15 (26.09/0.00/8.70/65.22) | 28/3/4/15 (56.00/6.00/8.00/30.00) | — |
Frameshift | Nonsense | Missense | Deletion |
P
frameshift-nonsense
|
P
frameshift -missense
|
P
nonsense-missense
| |
---|---|---|---|---|---|---|---|
N | 7 | 14 | 51 | 1 | |||
Male, n (%) | 5 (71.43%) | 11 (78.57%) | 27 (52.94%) | 0 (0.00%) | 1.00 × 10-0F | 4.42 × 10-1F | 1.27 × 10-1F |
Ethnicities Caucasian/East Asian/African, n (%) | 6/1/0 (85.71/14.29/0.00) | 9/4/1 (64.29/28.57/7.14) | 48/3/0 (94.12/5.88/0.00) | 1/0/0 (100.00/0.00/0.00) | 6.13 × 10-1Fa | 4.11 × 10-1Fa |
2.68 × 10
-2
F
a
|
Age at diagnosis (year) | 21.00 (17.00, 25.00) | 25.00 (19.00, 45.00) | 28.00 (23.00, 32.00) | 20.00 | Pframeshift-nonsense-missense = 1.81 × 10-1K | ||
Age at presentation (year) | 21.00 (17.00, 25.00) | 24.00 (19.00, 25.00) | 25.00 (21.00, 31.00) | — | Pframeshift-nonsense-missense = 2.34 × 10-1K | ||
Disease onset before 30 years, n (%) | 7 (100.00%) | 9 (64.29%) | 37 (72.55%) | 1 (100.00%) | 1.24 × 10-1F | 1.78 × 10-1F | 5.29 × 10-1F |
Serum parameters at presentation | |||||||
Serum ferritin (ng/ml) | 4840.00 (2800.00, 5999.00) | 2736.50 (1700.00, 7000.00) | 3728.0 (2500.00, 5574.50) | 1955.00 | Pframeshift-nonsense-missense = 6.93 × 10-1K | ||
Transferrin saturation (%) | 96.50 (94.00, 100.00) | 94.00 (89.50, 97.30) | 96.00 (90.00, 100.00) | — | Pframeshift-nonsense-missense = 3.73 × 10-1K | ||
Complications | |||||||
Cardiomyopathy, n (%) | 3 (42.86%) | 6 (42.86%) | 18 (35.29%) | 1 (100.00%) | 1.00 × 10-0F | 6.96 × 10-1F | 6.04 × 10-1C |
Skin hyperpigmentation, n (%) | 2 (28.57%) | 7 (50.00%) | 20 (39.22%) | 1 (100.00%) | 6.42 × 10-1F | 6.98 × 10-1F | 4.68 × 10-1C |
Arthropathy, n (%) | 0 (0.00%) | 2 (14.29%) | 15 (29.41%) | 1 (100.00%) | 5.33 × 10-1F | 1.73 × 10-1F | 3.23 × 10-1F |
Endocrine abnormality | |||||||
Hypogonadism, n (%) | 6 (85.71%) | 5 (35.71%) | 37 (72.55%) | 1 (100.00%) | 6.35 × 10-2F | 6.64 × 10-1F |
2.43 × 10
-2
F
|
Glucose intolerance, n (%) | 3 (42.86%) | 7 (50.00%) | 12 (23.53%) | 0 (0.00%) | 1.00 × 10-0F | 3.60 × 10-1F | 5.37 × 10-2C |
Osteopathy, n (%) | 0 (0.00%) | 0 (0.00%) | 4 (7.84%) | 1 (100.00%) | — | 1.00 × 10-0F | 1.00 × 10-0F |
Thyroid abnormality, n (%) | 0 (0.00%) | 1 (7.14%) | 2 (3.92%) | 0 (0.00%) | 1.00 × 10-0F | 1.00 × 10-0F | 5.23 × 10-1F |
Liver disease | |||||||
Abnormal liver function test, n (%) | 3 (42.86%) | 4 (28.57%) | 19 (37.25%) | 1 (100.00%) | 6.38 × 10-1F | 1.00 × 10-0F | 7.54 × 10-1F |
Liver iron deposition, n (%) | 5 (71.43%) | 11 (78.57%) | 33 (64.71%) | 1 (100.00%) | 1.00 × 10-0F | 1.00 × 10-0F | 5.20 × 10-1F |
Liver fibrosis, n (%) | 5 (71.43%) | 3 (21.43%) | 24 (47.06%) | 0 (0.00%) | 5.55 × 10-2F | 4.23 × 10-1F | 1.27 × 10-1F |
Liver cirrhosis, n (%) | 2 (28.57%) | 3 (21.43%) | 14 (27.45%) | 1 (100.00%) | 1.00 × 10-0F | 1.00 × 10-0F | 7.45 × 10-1F |
Liver biopsy, n (%) | 6 (85.71%) | 4 (28.57%) | 31 (60.78%) | 1 (100.00%) |
2.37 × 10
-2
F
| 4.03 × 10-1F |
3.93 × 10
-2
F
|
Therapy Phlebotomy/Chelating agent/Phlebotomy & Chelating agent/ND, n (%) | 3/0/1/3 (42.86/0.00/7.14/42.86) | 9/1/0/4 (64.29/7.14/0.`00/28.57) | 21/2/5/23 (41.18/3.92/9.80/45.10) | 1/0/0/0 (100.00/0.00/0.00/0.00) | — | — | — |