Transcript Familial Hypercholesterolaemia in Scotland

Catriona Brown
Zosia Miedzybrodzka
Margaretha Van Mourik
NICE Guidelines FH
 The prevalence of heterozygous FH in the UK
population is estimated to be 1 in 500,
 ~110,000 people are affected
 ↑ serum cholesterol concentration characterises
heterozygous FH
 It leads to >50% risk of coronary heart disease in
men by the age of 50 years and at least 30% in
women by the age of 60 years.
NICE Guidelines FH
 Family history of premature coronary heart disease
should always be assessed in a person being considered
for a diagnosis of FH (see Simon Broome criteria)
 In children at risk of FH because of one affected parent,
the following diagnostic tests should be carried out by the
age of 10 years
− A DNA test if the family mutation is known
− LDL-C concentration measurement if the family
mutation is not known.
 A further LDL-C measurement should be repeated after
puberty because LDL-C concentrations change during
puberty
Simon Broome diagnostic criteria
for index individuals
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Diagnose a person with definite familial hypercholesterolaemia (FH) if they have:
• cholesterol concentrations as defined in table 1 and tendon xanthomas, or evidence of these
signs in first- or second-degree relative
OR
• DNA-based evidence of an LDL-receptor mutation, familial defective apo B-100, or a PCSK9
mutation.
Diagnose a person with possible FH if they have cholesterol concentrations as defined in table 1
and at least one of the following.
• Family history of myocardial infarction: aged younger than 50 years in second-degree relative or
aged younger than 60 years in first-degree relative.
• Family history of raised total cholesterol: greater than 7.5 mmol/l in adult first- or second-degree
relative or greater than 6.7 mmol/l in child, brother or sister aged younger than 16 years.
Table 1 Cholesterol levels to be used as diagnostic criteria for the index individual1
Total cholesterol
LDL-C
Child/young person
> 6.7 mmol/l
> 4.0 mmol/l
Adult
> 7.5 mmol/l
> 4.9 mmol/l
1 Levels either pre-treatment or highest on treatment.
LDL-C, low-density lipoprotein cholesterol.
NICE Guidelines FH - Identifying people with FH
using cascade testing
 Healthcare professionals should offer all people with FH
a referral to a specialist with expertise in FH for
- confirmation of diagnosis
- initiation of cascade testing
 Cascade testing using a combination of DNA testing and
LDL-C concentration measurement is recommended
 This should include at least the first- and second- and,
when possible, third-degree biological relatives
The Scottish FH Working Party
 Established Nov 2008
 Met January 2009, due to meet again soon
 Discussion document from Scottish FH Working Party
 Patient information sheet
 Laboratory request form
 Consent form
 Cascade testing form
Website under construction
Agreed protocol
 Eligible for testing: Simon Broome criteria positive
 Lipid clinics to select patients for testing
 Genetics to do the cascade
Map of lipid clinic locations
Lipid Clinics in Scotland
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Ayrshire & Arran- Ayr Hospital (south), Crosshouse
Borders- Edinburgh Royal Infirmary
Dumfries and Galloway- Dumfries and Galloway Royal Infirmary
Fife – Victoria Hospital
Forth Valley- Falkirk Infirmary, Stirling Infirmary
Grampian-Aberdeen Royal Infirmary
Greater Glasgow and Clyde-Royal Infirmary Glasgow, Southern
General, Western infirmary, Gartnaval General
Highland- Raigmore tba
Lothian and Borders - St Johns Hospital (west), Edinburgh Royal
Infirmary
Orkney- Outreach from Aberdeen Royal Infirmary
Shetland- Outreach from Aberdeen Royal Infirmary
Tayside- Ninewells Hospital Dundee
Vale of Leven- Clyde and Paisley
Western Isles- Raigmore & Glasgow?
Aberdeen Lab Results
 After a slow start, there has been an increase in the
number of samples received - 34 of the 62 have
been since April 1st 2009
 All of the samples that have been reported were
within the 8 week reporting time
 There have been no follow up samples sent in yet for
the testing of a familial mutation
62 Samples received have been from :
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Aberdeen - 9
Auchterarder - 1
Dumbartonshire - 13
Dundee - 5
Dunoon - 1
Edinburgh - 9
Falkirk - 3
Glasgow - 8
Greenock - 1
Inverness - 2
Livingston - 7
Paisley - 3
Summary of FH mutations Identified as of 22/05/09
 22 have no mutation identified
 2 have the common APOB mutation (c.10580G>A ;
p.Arg3527Gln)
 0 have the common PCSK9 mutation ( c.1120G>T ;
p.Asp374Tyr)
 5 have large scale deletions or duplications of LDLR identified
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by MLPA –
1 duplication of LDLR exon 11 & 12
1 deletion of LDLR exon 15
2 deletions of LDLR exon 2-18
1 deletion of LDLR exon 9-14
Summary of FH mutations Identified as of 22/05/09
 16 have mutations in the LDLR gene –
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c.682G>T (p.Glu228X)
c.1090T>C (p.Cys364Arg) x 2
c.1359-31delGCGCTGATinsCGGCT
c.418G>A (p.Glu140Lys)
c.693C>A (p.Cys231X)
c.551G>A (p.Cys184Tyr)
c.1745T>C (p.Leu582Pro)
c.660delC (p.Pro220ProfsX45) x 3
c.1238C>T (p.Thr413Met)
c.2029T>C (p.Cys677Arg)
c.301G>A (p.Glu101Lys)
**c.1813C>T (p.Leu605Leu) x2
** Found in mother and son in silico analysis suggests may affect splicing of
the LDLR gene by creating a cryptic donor site. Fresh blood samples for
RNA work was requested.
Agreed protocol
Eligible for testing: Simon Broome criteria positive
Lipid clinics to select patients for testing
Genetics to do the cascade
Qs:
Should we accept screen referrals from other clinicians
suggest yes if SB criteria proven to be met, use lipid drs to
help to implement- AGREED YES BUT AUDIT
?do we a national db for cascade screening or should we use
existing systems- does FH deserve more than the rest???
COLLECT DATA AS PLANNED MEANTIME BUT CONTINUE
TO EXPLORE NEEDS THROUGH WORKING PARTY
FORMS TO SCOTGEN SITE