Hemochromatosis (HFE)

Hemochromatosis (HFE) 3 Variants Indications for Ordering • Early clinical symptoms (nonspecific) o Joint pain, stiffness • Confirm clinical diagnosis of hereditary hemochromatosis o Abdominal pain (HH) in an individual with biochemical findings of iron o Fatigue, lethargy overload o Weight loss • Screen adult family members of individuals with known • Without treatment HH o Liver disease (cirrhosis, fibrosis, hepatocellular • Test reproductive partner of an individual with HH for carcinoma) carrier status o Skin hyperpigmentation • Not recommended for initial hemochromatosis testing o Diabetes mellitus Test Description o Heart disease (arrhythmias, cardiomyopathy) o Hypogonadism • Polymerase chain reaction and fluorescence monitoring to o Arthritis detect three variants in the HFE gene • Early laboratory biochemical abnormalities include • p.C282Y (c.845G>A) elevated serum transferrin concentration • p.H63D (c.187C>G) • Early treatment will prevent complications, such as • p.S65C (c.193A>T) cirrhosis Tests to Consider Pathophysiology • Variant leads to high rate of iron absorption across Primary Test duodenal enterocytes Hemochromatosis (HFE) 3 Mutations 0055656 • Leads to excessive parenchymal storage of iron with end- • Genetic test for diagnosis of HH organ damage Related Biochemical Screening Tests Genetics Iron and Iron Binding Capacity 0020420 Gene: HFE • Initial screening test for iron overload • Includes calculated transferrin saturation Inheritance: autosomal recessive Ferritin 0070065 Variants • Initial screening test for iron overload • Allele frequency varies by ethnicity Disease Overview o C282Y . White: 0.11 Prevalence . Hispanic: 0.03 • 1/200-400 among White individuals (~1/3 carrier . African American: 0.02 frequency) . Asian: <0.01 • Lower in other ethnicities o H63D . White: 0.25 Age of Onset . Hispanic: 0.18 • Males: 40s-50s . Asian: 0.09 • Females: postmenopausal . African American: 0.06 Symptoms o S65C • Majority of individuals homozygous for HFE gene do not . White: 0.015 develop symptoms . Other: unknown • Variant frequency among White individuals with HH o C282Y homozygous: ~85% o C282Y/H63D compound heterozygous: ~5% o C282Y/S65C compound heterozygous: <1%

Test Interpretation Limitations Sensitivity/Specificity • Test should not be used for • Clinical sensitivity o Testing at-risk asymptomatic minors o Up to 90% for White populations (Seckington, 2015) o Population carrier screening o Lower in other ethnicities o Prenatal diagnosis • Analytical sensitivity/specificity: 99% • Rare diagnostic errors may occur due to primer-site variations Results • Only the three targeted HFE gene variants will be Interpretations for Common HFE Gene Variants analyzed Variant Patient presentation Comments • Genotyping does not substitute for serum iron studies, for clinical and which identify iron overload biochemical evidence of iron References overload C282Y, H63D, S65C May have elevated Negative clinical • Bacon BR, Adams PC, et al. Diagnosis and management of heterozygosity; serum iron levels symptoms of iron hemochromatosis: 2011 practice guideline by the H63D homozygosity overload American Association for the Study of Liver Positive clinical Consider HFE or other Diseases. Hepatology. 2011:54(1);328-343 symptoms only if an alternative full gene additional rare, • Seckington R, Powell L. HFE-Associated Hereditary sequencing and possibly undetected HFE variant Hemochromatosis. 2000 Apr 3 [Updated 2015 Sep 17]. In: deletion/duplication is present analysis if suspicion for Pagon RA, Adam MP, Ardinger HH, et al., editors. HH remains high GeneReviews [Internet]. Seattle (WA): University of C282Y Negative High risk for iron Washington, Seattle; 1993-2016 (www.ncbi.nlm.nih.gov/ homozygosity overload books/NBK1440/) Only minority develop clinical symptoms Positive Confirms diagnosis of HH

Only minority develop clinical symptoms C282Y/H63D; Negative Moderate risk of iron C282Y/S65C overload compound <2% risk of developing heterozygosity clinical symptoms Positive Supportive of diagnosis of HH Penetrance is low: only minority develop clinical symptoms

Negative • Lack of detection of one of three HFE variants does not eliminate the possibility of HH o Rare HFE variants and those in other iron-related genes are not detected by this test