Update to: European Journal of Human Genetics (2012) 20, doi:10.1038/ejhg.2012.85; published online 16 May 2012

1. Disease characteristics

1.1 Name of the disease (synonyms)

Familial hypobetalipoproteinaemia (Familial hypobetalipoproteinaemia type 1).

1.2 OMIM# of the disease

615558.

1.3 Name of the analysed genes or DNA/chromosome segments

APOB.

1.4 OMIM# of the gene(s)

107730.

1.5 Mutational spectrum

Over 90 variants have been reported, mostly nonsense and frameshift, occurring throughout the 29 exons of APOB.1, 2, 3, 4 Missense variants affecting the amino terminal region of the apolipoprotein B (apoB) protein have also been described in familial hypobetalipoproteinaemia.5

1.6 Analytical methods

DNA sequencing of genomic-exonic DNA with at least 20 bp of flanking intronic sequence. Western blotting can be used to detect truncated apoB species that are >30% of full-length protein size, to estimate where the variant occurs within APOB. If western blotting is negative, sequencing of the 5' 30% of the gene (exons 1 through 25) is recommended. Where homozygous familial hypobetalipoproteinaemia is suspected and a variant(s) in APOB cannot be found, consider sequencing MTTP.

1.7 Analytical validation

Where a variant is identified using bi-directional DNA sequencing, the test should be repeated from a fresh dilution of DNA for confirmation. For homozygous familial hypobetalipoproteinaemia, testing of the patient's parents is recommended, to confirm that the two variants are present in trans (ie, on opposite chromosomes).

1.8 Estimated frequency of the disease

(Incidence at birth (‘birth prevalence’) or population prevalence)

Approximately 1 in 1000–3000 are estimated to carry apoB truncations (heterozygous familial hypobetalipoproteinaemia).6

1.9 If applicable, prevalence in the ethnic group of investigated person

Not applicable.

1.10 Diagnostic setting

Comment: Familial hypobetalipoproteinaemia is primarily a biochemical diagnosis; heterozygotes have plasma apoB levels one-quarter to one-third of normal, while in homozygotes apoB is very low or undetectable. Prenatal diagnosis may be required by parents who are both known to carry short truncations leading to severe apoB deficiency.

2. Test characteristics

2.1 Analytical sensitivity

(proportion of positive tests if the genotype is present)

Approximately 100%.

2.2 Analytical specificity

(proportion of negative tests if the genotype is not present)

Approximately 100%.

2.3 Clinical sensitivity

(proportion of positive tests if the disease is present) The clinical sensitivity can be dependent on variable factors such as age or family history. In such cases a general statement should be given, even if a quantification can only be made case by case.

Many factors, such as a strict vegan diet, illness and high-dose statin therapy, can cause hypobetalipoproteinaemia. The more common secondary causes in the hospital setting include cachexia, malabsorption, malnutrition, severe liver disease and hyperthyroidism. Familial hypobetalipoproteinaemia is characterised by low levels (<5th percentile for age and sex) of plasma apoB-containing lipoproteins.1,2 It has been suggested that familial hypobetalipoproteinaemia might represent a longevity syndrome and be associated with cardiovascular protection due to resistance to atherosclerosis. Heterozygotes are usually asymptomatic with low-density lipoprotein (LDL) cholesterol and apoB concentrations approximately one-third of those in normal plasma. Most of them have increased serum aminotransaminases due to hepatic steatosis and sometimes mild fat malabsorption.

Homozygous familial hypobetalipoproteinaemia is biochemically characterised by the absence of apoB-containing lipoproteins from plasma. The clinical features may resemble those of abetalipoproteinaemia: fat malabsorption, fatty liver, acanthocytosis, retinitis pigmentosa, spinocerebellar ataxia and myopathy, particularly in those with truncating variants shorter in length than apoB-48. Should this constellation of findings be present there are two possibilities, homozygous familial hypobetalipoproteinaemia or abetalipoproteinaemia caused by variants in MTTP. Family screening is useful in delineating between these conditions, as while obligate heterozygote parents of abetalipoproteinaemia patients have normal plasma lipid profiles, obligate heterozygous parents of homozygous familial hypobetalipoproteinaemia patients have plasma LDL cholesterol and apoB concentrations approximately one-third of normal.

2.4 Clinical specificity

(proportion of negative tests if the disease is not present) The clinical specificity can be dependent on variable factors such as age or family history. In such cases a general statement should be given, even if a quantification can only be made case by case.

Approximately 100%.

2.5 Positive clinical predictive value

(life time risk to develop the disease if the test is positive)

100%.

2.6 Negative clinical predictive value

(Probability not to develop the disease if the test is negative) Assume an increased risk based on family history for a non-affected person. Allelic and locus heterogeneity may need to be considered.

Index case in that family had been tested:

100%.

Index case in that family had not been tested:

Should the constellation of clinical findings be present in an index case, it is possible that they might have abetalipoproteinaemia, rather than homozygous familial hypolipoproteinaemia. Abetalipoproteinaemia patients receive similar treatment advice as homozygous familial hypobetalipoproteinaemia patients. Also, there are even rarer conditions called homozygous proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency and familial combined hypolipidaemia (due to homozygous variants in angiopoietin-like protein 3, ANGPTL3) that present with extremely low (but not absent) levels of apoB-containing lipoproteins, but no systemic manifestations.2 In familial combined hypolipidaemia, high-density lipoprotein (HDL) cholesterol levels are also very low. To date, there are only a handful of families in the world reported with these latter two genetic conditions.

3. Clinical utility

3.1 (Differential) diagnostics: The tested person is clinically affected

(To be answered if in 1.10 ‘A’ was marked)

3.1.1 Can a diagnosis be made other than through a genetic test?

3.1.2 Describe the burden of alternative diagnostic methods to the patient

Heterozygotes for familial hypobetalipoproteinaemia are often asymptomatic, but have plasma LDL cholesterol and apoB concentrations that are approximately one-third of normal. Most of them have increased serum aminotransferases due to hepatic steatosis and sometimes mild fat malabsorption.7,8 Homozygous familial hypobetalipoproteinaemia is characterised by the absence of plasma apoB-containing lipoproteins with marked hypocholesterolaemia, absence of LDL cholesterol and apoB and low triglyceride concentrations. In addition, increased serum aminotransferases due to hepatic steatosis, acanthocytosis and fat-soluble vitamin deficiency are found. Homozygous familial hypobetalipoproteinaemia, particularly those with truncating variants shorter in length than apoB-48, cannot be distinguished from abetalipoproteinaemia clinically.

3.1.3 How is the cost effectiveness of alternative diagnostic methods to be judged?

Not applicable.

3.1.4 Will disease management be influenced by the result of a genetic test?

3.2 Predictive setting: The tested person is clinically unaffected but carries an increased risk based on family history

(To be answered if in 1.10 ‘B’ was marked)

3.2.1 Will the result of a genetic test influence lifestyle and prevention?

If the test result is positive (please describe).

If the test result is negative (please describe).

3.2.2 Which options in view of lifestyle and prevention does a person at-risk have if no genetic test has been done (please describe)?

Not applicable.

3.3 Genetic risk assessment in family members of a diseased person

(To be answered if in 1.10 ‘C’ was marked).

3.3.1 Does the result of a genetic test resolve the genetic situation in that family?

Not applicable.

3.3.2 Can a genetic test in the index patient save genetic or other tests in family members?

Not applicable.

3.3.3 Does a positive genetic test result in the index patient enable a predictive test in a family member?

Not applicable.

3.4 Prenatal diagnosis

(To be answered if in 1.10 ‘D’ was marked).

3.4.1 Does a positive genetic test result in the index patient enable a prenatal diagnosis?

Not applicable.

4. If applicable, further consequences of testing

Please assume that the result of a genetic test has no immediate medical consequences. Is there any evidence that a genetic test is nevertheless useful for the patient or his/her relatives? (Please describe)