title: EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH).
abstract: Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines.
authors.affiliation: Center for Predictive and Preventive Genetics (CGPP), Institute of Molecular and Cellular Biology (IBMC), Porto, Portugal.|Clinical Haematology, Hospital Santo António (CHP-HAS) and Department of Molecular Pathology and Immunology, Abel Salazar Institute for Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal.
authors.forename: Graça
authors.initials: G
authors.lastname: Porto
authors.affiliation: Liver Disease Unit, Pontchaillou University Hospital, University of Rennes, and National Reference Centre for Rare Iron Overload Diseases of Genetic Origin, Rennes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Brissot
authors.affiliation: Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Dorine W
authors.initials: DW
authors.lastname: Swinkels
authors.affiliation: Department of Medicine II, Gastroenterology and Hepatology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Zoller
authors.affiliation: European Molecular Quality Network (EMQN), Manchester, UK.
authors.forename: Outi
authors.initials: O
authors.lastname: Kamarainen
authors.affiliation: European Molecular Quality Network (EMQN), Manchester, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Patton
authors.affiliation: Center for Predictive and Preventive Genetics (CGPP), Institute of Molecular and Cellular Biology (IBMC), Porto, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Alonso
authors.affiliation: European Molecular Quality Network (EMQN), Manchester, UK.|Synlab, Lausanne, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Morris
authors.affiliation: European Molecular Quality Network (EMQN), Manchester, UK.|Molecular Diagnostics Centre (Haematology), Manchester Royal Infirmary, Manchester, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Keeney
mesh_terms: D005820:Genetic Testing / Q000379:methods* / Q000592:standards; D006432:Hemochromatosis / Q000175:diagnosis / Q000235:genetics*; D000071020:Hemochromatosis Protein / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D025202:Molecular Diagnostic Techniques / Q000379:methods* / Q000592:standards; D020125:Mutation, Missense
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein