Hereditary haemochromatosis

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PRACTICE POINT

Hereditary haemochromatosis (HHC) is a common condition that affects an estimated one in 200 individuals of northern European background. Genetic testing for HHC should be performed in patients with proven iron overload. Cascade screening Cascade screening involves testing the close biological relatives of an individual who has or is a carrier of a genetic condition in order to determine whether these relatives carry the genetic variant or chromosomal alternation (thereby increasing their chances of developing the condition or having a child with the condition). For example, cascade testing is available under the Medicare Benefits Schedule for genetic testing for familial hypercholesterolaemia. of relatives is also important when specific gene variants Gene variants are small DNA sequence changes (ie additions, duplications, deletions, substitutions). These variants can have a range of effects: some may cause disease (pathogenic variant), while others do not cause disease but may modify an individual’s risk of disease (i.e may increase risk or provide a protective effect). The vast majority of gene variants are benign and do not result in disease but rather contribute to the differences between people. causing HHC are confirmed in the family.

Screening for HHC in the general population is currently not recommended given its variable expressivity and incomplete penetrance.

What do I need to know?

HHC is a condition with autosomal recessive inheritanc When a condition follows an autosomal dominant pattern of inheritance, the family tree will usually reveal multiple affected members in multiple generations on the same side of the family. Dominant conditions or traits are expressed when only a single gene variant is inherited. Wide variability in clinical expression is common in many autosomal dominant conditions, even within the same family. Early onset of conditions, such as cancer, can be indicative of autosomal dominant inheritance within a family. Not all dominant conditions show 100% penetrance (eg BRCA1 gene mutations). in which excessive iron absorption leads to increased body iron stores. HHC is underdiagnosed as the symptoms are usually non-specific; however, early diagnosis and treatment reduces serious complications and possible early death.

The most common genetic cause of HHC (up to 90%) is homozygosity Homozygosity refers to the presence of two identical alleles (form of a gene variant) at a given location on a pair of chromosomes. of the p.Cys282Tyr (previously known as C282Y) gene variant in the HFE gene (HFE- haemochromatosis). About one in 10 people are carriers of a p.Cys282Tyr variant, while one in every 200 people is homozygous for the p.Cys282Tyr variant. Another common variant in the HFE gene is p.His63Asp (previously known as H63D). Not all individuals with a genetic predisposition to HHC will develop iron overload (incomplete penetrance).

The risk of iron overload varies according to genotype (Table 1).

Table 1. Varying genotypes and risk of iron overload

Genotype	Risk of iron overload with genotype	Frequency of genotype*
Heterozygous p.Cys282Tyr (previously known as C282Y)	No increased risk	1 in 10
Homozygous p.Cys282Tyr (previously known as C282Y)	Greatly increased risk – 40–60% for females and 75–100% for males	1 in 200
Heterozygous p.His63Asp (previously known as H63D)	No increased risk	1 in 4
Homozygous p.His63Asp (previously known as H63D)	No increased risk	1 in 50
Compound heterozygous p.Cys282Tyr/ p.His63Asp (previously known as C282Y/H63D)	Small increase in risk – 1%	1 in 50

*Frequency data are approximate for those of northern European ancestry and ethnicity.

Genetic testing

Genetic testing for the risk of HHC is recommended in individuals with suspected iron overload (ie elevated serum ferritin concentration >200 µg/L [(females)] or >300 µg/L [(males)], and a transferrin saturation >45%).

Cascade screening is warranted for all first-degree relatives of patients with HHC who are p.Cys282Tyr homozygous or p.Cys282Tyr/ p.His63Asp compound heterozygous.

A Medicare Benefits Schedule (MBS) rebate for the HFE gene test applies where the patient has an elevated transferrin saturation or elevated serum ferritin on repeat testing or has a first-degree relative with haemochromatosis or is homozygous for the p.Cys282Tyr gene variant or is compound heterozygous for p.Cys282Tyr/ p.His63Asp.

Other considerations

Asymptomatic individuals (identified through cascade screening) who are p.Cys282Tyr homozygous or p.Cys282Tyr/ p.His63Asp compound heterozygous should have their serum ferritin regularly monitored.

Patients with HFE-haemochromatosis should be encouraged to:

inform all first-degree relatives of increased risk
direct family to information about haemochromatosis (eg Haemochromatosis Australia)
advise family members to discuss their risk with their general practitioner (GP)
be blood donors.