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A Simple Genetic Test Identifies 90% of UK Patients with Haemochromatosis

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A Simple Genetic Test Identifies 90% of UK Patients with Haemochromatosis Gut 1997; 41: 841–844 841 A simple genetic test identifies 90% of UK patients with haemochromatosis Gut: first published as 10.1136/gut.41.6.841 on 1 December 1997. Downloaded from The UK Haemochromatosis Consortium Abstract tended “ancestral” haplotype of chromosome 6 Background—The diagnosis of genetic microsatellite marker alleles (D6S265-1, haemochromatosis (GH) before iron over- D6S105-8, D6S1260-4 which includes HLA- load has developed is diYcult. However a A3), reflecting the haplotype of the founder convincing candidate gene for GH, HFE mutation.6 In the absence of information about (previously HLA-H), has been described the biochemical defect in genetic haemochro- recently. matosis, positional cloning has been used in the Aims—To determine the prevalence of the search for the gene. Recently, we showed that haemochromatosis associated HFE muta- the gene mapped telomeric to HLA-A, close to tions C282Y and H63D in United Kingdom the microsatellite marker D6S1260.6 Extension aVected and control populations. of this approach led to the identification of a Methods—The prevalence of the HFE strong candidate gene for genetic haemochro- C282Y and H63D mutations was deter- matosis, termed HFE7 (previously HLA-H). mined by polymerase chain reaction am- The direct evidence on which this claim was plification and restriction enzyme based centred on the high frequency (83%) of digestion in a cohort of 115 well character- US patients with genetic haemochromatosis ised patients with GH and 101 controls homozygous for a single mutation (C282Y), from the United Kingdom. the association of this mutation with the ances- Results—One hundred and five of 115 tral haplotype, and the proposed functional (91%) patients with GH were homozygous consequences of this mutation. We have for the C282Y mutation. Only one of 101 studied the prevalence of mutations in this (1%) controls was homozygous for the gene in a cohort of UK patients with genetic C282Y mutation and this individual cur- haemochromatosis identified by strict diagnos- rently shows evidence of iron overload. tic criteria. Two of five patients who did not have either of the two described mutations of HFE had early onset iron overload (ages http://gut.bmj.com/ 16 and 24). One had a family history of Patients and Methods cardiac failure and the second was subse- DNA was prepared from blood samples quently hospitalised due to cardiac fail- obtained from patients with haemochromatosis ure. These are the first phenotypic diagnosed and managed at four UK centres observations for patients without either (King’s College Hospital, Royal Free Hospital, C282Y or H63D mutation of HFE. John RadcliVe Hospital, and the University Conclusion—This simple genetic test Hospital of Wales). The diagnosis of genetic on September 28, 2021 by guest. Protected copyright. promises to be a highly eVective tool in the haemochromatosis was confirmed on the basis diagnosis of GH. of a hepatic iron index of greater than 1.9, or (Gut 1997; 41: 841–844) greater than 5 g mobilisable iron by quantita- tive phlebotomy, in the absence of any other Keywords: haemochromatosis; genetic testing; HFE; HLA-H; C282Y; H63D; iron overload cause of iron loading. Thirty five per cent of the 115 patients with genetic haemochromatosis studied had at least one other known aVected Genetic haemochromatosis is an autosomal family member. Control samples were ob- recessive disorder resulting in iron overload. In tained from a series of 101 healthy blood northern European populations, where the dis- donors from South Wales.8 ease is believed to have originated, as many as HFE gene analysis was performed by 1 in 300 individuals are aVected.12 Unrecog- polymerase chain reaction (PCR) amplification nised, the iron loading results in tissue damage of total genomic DNA of the two regions of the aVecting the liver, pancreas, joints, anterior HFE gene carrying the mutations C282Y and pituitary, and heart.3 Early diagnosis and treat- H63D.7 The G to A transition (aa282) creates ment by repeated venesection is eVective and a new RsaI site; there is a second RsaI site in restores normal life expectancy.4 However, this fragment which acts as an internal control Correspondence to: detection of sporadic genetic haemochromato- in the restriction fragment length polymor- Dr K J H Robson, MRC sis in the early, asymptomatic phase may be phism (RFLP) analysis. The C to G transver- Molecular Haematology sion (aa63) results in the loss of BclI and MboI Unit, Institute of Molecular diYcult in the absence of a reliable test. Medicine, John RadcliVe Simon et al showed that the gene responsible sites in the amplified product allowing typing Hospital, Headington, for genetic haemochromatosis mapped close to by RFLP.Results were confirmed by relocating Oxford OX3 9DU, UK. the major histocompatibility complex (MHC) the 3' primer (5' CTT GCT GTG GTT GTG 5 Accepted for publication locus HLA-A (6p21.3). About 50% of genetic ATT TTC C 3') to include a second MboI site, 2 June 1997 haemochromatosis chromosomes carry an ex- thus providing an internal control. 842 UK Haemochromatosis Consortium TABLE 1 Genotype frequencies for mutations in HLA-H (TIBC) 33 µmol/l, ferritin 3350 µg/l), myocar- dial biopsy, and the quantitation of iron Genotypes overload. Initial desferrioxamine treatment for Gut: first published as 10.1136/gut.41.6.841 on 1 December 1997. Downloaded from HH/YY HH/CC HD/CC HD/CY HH/CY DD/CC Total 52 days removed 3.5 g iron. Venesection therapy, commenced in parallel with the iron GH 105 5 0 3 1 1 115 chelation, was continued over 13.5 months Controls 1 65 22 4 6 3 101 removing an additional 11 g iron. In total, Genotypes are given for amino acid 63/amino acid 282 of the polypeptide (C, cysteine; D, aspar- 14.5 g iron was removed in 13.5 months. tic acid; H, histidine; Y, tyrosine). HH/CC = normal (wild type) and HH/YY = homozygosity for Patient 1 has had no transfusions, and has no the C282Y mutation. GH, genetic haemochromatosis. known family history, as he is adopted. His Results genotype (D6S265 1,3; D6S105 6,8; D6S1260 One hundred and fifteen unrelated patients 3,4; D6S1621 5,6) does not provide suYcient with genetic haemochromatosis and 101 con- information to exclude the possible presence of trols were genotyped (table 1). The frequency one copy of the ancestral haplotype, but reveals of the C282Y mutation was 93% and 6% in that he is not homozygous for the ancestral patient and control chromosomes respectively. haplotype. Homozygosity for this mutation was seen in Patient 2 was diagnosed at the age of 16 dur- 91% of patients and only 1% of controls. ing family screening. His elder brother had Homozygosity for the C282Y mutation was presented at age 21 with gross heart failure and seen in 38/40 patients with genetic haemochro- on investigation was found to have micronodu- matosis with a positive family history, which lar cirrhosis and massive iron overload on liver was not significantly diVerent from 67/75 biopsy. The brother had died of an asystolic patients with genetic haemochromatosis with- cardiac arrest while in hospital before treat- out a family history (÷2=0.046, p=0.50). Of the ment could be started. On biochemical screen- 99 patients for which we had full haplotype ing patient 2 was found to have a serum iron information, 23 were homozygous for the concentration of 42 µmol/l, TIBC of 44 µmol/l, extended ancestral haplotype (D6S265-1, ferritin of 2082 µg/l, and on liver biopsy grade D6S105-8, D6S1260-4 which includes HLA- 4 siderosis but minimal fibrosis. He has no A3) and homozygous for the C282Y mutation. abnormality of copper metabolism as deter- The H63D variant was present in 2% of mined by biochemical analysis. He became haemochromatosis and 16% of control chro- iron deficient after the removal of 10 g iron by mosomes. One patient and three controls venesection and during the follow up period of were homozygous for this variant. There was 20 years required regular venesection to main- no evidence of iron loading in these three tain normal iron indexes. Microsatellite analy- controls. sis for patient 2 revealed a haplotype (D6S265 None of the patients homozygous for the 3,6; D6S105 6,8; D6S1260 4,4; D6S1621 C282Y mutation carried the H63D variant. 7,10) in which neither chromosome demon- http://gut.bmj.com/ However, three patients and four controls were strates the founder haplotype. heterozygous for both the C282Y and H63D mutations (compound heterozygotes). These Discussion three compound heterozygote patients had We confirm the remarkably strong association mild disease as evidenced by initial quantitative between the C282Y mutation in HFE and phlebotomy removing circa 5 g iron. The four genetic haemochromatosis as recently re- controls who were compound heterozygotes ported.7 The observed homozygosity for this on September 28, 2021 by guest. Protected copyright. showed no signs of iron loading. mutation was higher in this sample of UK Four of the six haemochromatotic patients haemochromatosis patients than that reported without the C282Y mutation had clinical and in the original sample from the USA (91% ver- biochemical features typical of genetic haemo- sus 83%, ÷2=3.95, p=0.047). Recent reports chromatosis (table 2). The remaining two have confirmed the high frequency of homozy- however had early onset of iron overload. gosity for the C282Y mutation in patients with Patient 1 was diagnosed with heart failure at 29 genetic haemochromatosis, and reveal consist- years of age. On reviewing his history, he had ent results in similar populations. Thus, two displayed features of hypogonadotropic hy- American studies have now reported 83% and pogonadism five years earlier (age 24).
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